Selective anthranilamide pyridine amides as inhibitors of vegfr-2 and vegfr-3

ABSTRACT

Selective anthranilamide pyridinamides as VEGFR-2 and VEGFR-3 inhibitors, their production and use as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis are described. The compounds according to the invention can be used as or in the case of psoriasis, Kaposi&#39;s sarcoma, restenosis, such as, e.g., stent-induced restenosis, endometriosis, Crohn&#39;s disease, Hodgkin&#39;s disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such as diabetic retinopathy, neovascular glaucoma; renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver, mesangial cell proliferative diseases, arteriosclerosis, injuries to nerve tissue, and inhibition of the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after mechanical devices are used to keep vessels open, such as, e.g., stents, as immunosuppressive agents, as a support in scar-free healing, senile keratosis and contact dermatitis. The compounds according to the invention can also be used as VEGFR-3 inhibitors in the case of lymphangiogenesis in hyper- and dysplastic changes of the lymphatic system.

[0001] The invention relates to selective anthranilamide pyridinamidesas VEGFR-2 and VEGFR-3 inhibitors, their production and use aspharmaceutical agents for treating diseases that are triggered bypersistent angiogenesis.

[0002] Persistent angiogenesis can be the cause of various diseases,such as psoriasis; arthritis, such as rheumatoid arthritis, hemangioma,endometriosis, angiofibroma; eye diseases, such as diabetic retinopathy,neovascular glaucoma; renal diseases, such as glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathic syndrome, transplant rejections and glomerulopathy;fibrotic diseases, such as cirrhosis of the liver, mesangial cellproliferative diseases and arteriosclerosis or can result in anaggravation of these diseases.

[0003] Persistent angiogenesis is induced by the factor VEGF via itsreceptor. So that VEGF can exert this action, it is necessary that VEGFbind to the receptor, and a tyrosine phosphorylation is induced.

[0004] Direct or indirect inhibition of the VEGF receptor (VEGF=vascularendothelial growth factor) can be used for treating such diseases andother VEGF-induced pathological angiogenesis and vascular permeableconditions, such as tumor vascularization. For example, it is known thatthe growth of tumors can be inhibited by soluble receptors andantibodies against VEGF.

[0005] Anthranilic acid amides that are used as pharmaceutical agentsfor treating psoriasis; arthritis, such as rheumatoid arthritis,hemangioma, angiofibroma; eye diseases, such as diabetic retinopathy,neovascular glaucoma; renal diseases, such as glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thrombicmicroangiopathic syndrome, transplant rejections and glomerulopathy;fibrotic diseases, such as cirrhosis of the liver, mesangial cellproliferative diseases, arteriosclerosis, injuries to nerve tissue, andfor inhibiting the reocclusion of vessels after balloon cathetertreatment, in vascular prosthetics or after mechanical devices are usedto keep vessels open, such as, e.g., stents, are known from WO 00/27819.

[0006] Strong angiogenesis is a prerequisite for the proliferation ofthe extrauterine endometrium in the case of endometriosis. Angiogenesisinhibition can therefore also be used for the treatment of this form ofdisease that causes painful conditions and often results in infertility.

[0007] The known compounds are generally effective in the indicationscited, but their effectiveness generally accompanies toxicity and aninferior compatibility of the medication.

[0008] There is therefore a desire, on the one hand, for more effectivecompounds, and, on the other hand, for more toxicologically harmlesscompounds, which, moreover, should also be more compatible.

[0009] It has now been found that compounds of general formula I

[0010] in which

[0011] A, B and D, independently of one another, stand for a nitrogen orcarbon atom, whereby at least one nitrogen atom is contained in thering,

[0012] E stands for aryl or hetaryl that is optionally substituted inone or more places in the same way or differently with halogen, cyano,C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl or with the group —OR⁵,—SR⁴, —SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴,—SO₂R⁴, —SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹,

[0013] G stands for a nitrogen atom or for the group —C—X,

[0014] L stands for a nitrogen atom or for the group —C—X,

[0015] M stands for a nitrogen atom or for the group —C—X,

[0016] Q stands for a nitrogen atom or for the group —C—X, whereby atmost one nitrogen atom is in the ring,

[0017] X stands for hydrogen, halogen or for C₁-C₆-alkyl, C₁-C₆-alkyloxyor C₁-C₆-carboxyalkyl that is unsubstituted or optionally substituted inone or more places with halogen,

[0018] R¹ stands for branched or unbranched C₁-C₁₂-alkyl orC₂-C₁₂-alkenyl that is optionally substituted in one or more places inthe same way or differently with halogen, hydroxy, C₁-C₆-alkyloxy,aralkyloxy, C₁-C₆-alkyl and/or with the group —NR²R³; or forC₃-C₁₀-cycloalkyl or C₃-C₁₀-cycloalkenyl that is optionally substitutedin one or more places in the same way or differently with halogen,hydroxy, C₁-C₆-alkyloxy, C₁-C₆-alkyl and/or with the group —NR²R³; orfor aryl or hetaryl that is optionally substituted in one or more placesin the same way or differently with halogen, cyano, hydroxy,C₁-C₆-alkyloxy, C₂-C₆-alkenyl, aryl-C₁-C₆-alkyloxy, aralkyloxy,C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group ═O, —SO₂R⁴, OR⁵, —R⁵ or—PO(OR¹²)(OR¹³),

[0019] R² and R³, independently of one another, stand for hydrogen orfor C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetarylthat is optionally substituted in one or more places in the same way ordifferently with halogen, cyano, C₁-C₆-alkyl, phenyl,hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, or with the group —NR⁶R⁷, —OR⁵,C₁-C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or

[0020] R² and R³, together with the nitrogen atom, form a C₃-C₈-ring,which optionally can contain another nitrogen, sulfur or oxygen atom inthe ring, or can contain the group —N(R¹⁰), and which optionally can besubstituted in one or more places in the same way or differently withhalogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group—OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴,

[0021] R⁴ stands for hydroxy, C₁-C₆-alkyl, aryl, heteroaryl or for thegroup —NR²R³,

[0022] R⁵ stands for hydrogen, C₁-C₁₋₂-alkyl, halo-C₁-C₆-alkyl,C₃-C₆-cycloalkyl or halo-C₃-C₆-cycloalkyl, or for C₁-C₁₂-alkyl, which isinterrupted in one or more places with oxygen or stands for the group—(CH₂)₂NR²R³, —CH₂CN or —CH₂CF₃,

[0023] R⁶ and R⁷, independently of one another, stand for hydrogen orC₁-C₆-alkyl, or

[0024] R¹ and R⁷ together form a 5- to 7-membered ring that can containan oxygen or sulfur atom or the group —N(R¹⁰)—,

[0025] R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl,aryl or hetaryl that is optionally substituted with halogen in one ormore places,

[0026] R⁹ stands for hydrogen, C₁-C₆-alkyl, tri-C₁₋₆-alkylsilyl, aryl,hetaryl or for the group —COR¹¹,

[0027] R¹⁰ stands for hydrogen, C₁-C₆-alkyl or aryl,

[0028] R¹¹ stands for hydrogen, C₁-C₆-alkyl or for the group —NR²R³, and

[0029] R¹² and R¹³, independently of one another, stand for hydrogen orC₁-C₆-alkyl, as well as isomers, enantiomers and salts thereof, overcomethe above-indicated drawbacks.

[0030] The compounds according to the invention prevent a tyrosinephosphorylation or stop persistent angiogenesis and thus the growth andpropagation of tumors, whereby they are distinguished in particular by aslighter inhibition of isoforms of Cytochrome P 450 (2C9 and 2C19).

[0031] Many pharmaceutical agents are degraded via these isoforms. In aninhibition of these isoforms, the plasma level of these pharmaceuticalagents increases, which can result in undesirable side effects.

[0032] Alkyl is defined in each case as a straight-chain or branchedalkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl, heptyl, octyl,nonyl, decyl, undecyl, or dodecyl.

[0033] Alkoxy is defined in each case as a straight-chain or branchedalkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy,isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy,undecyloxy or dodecyloxy.

[0034] Cycloalkyls are defined as monocyclic alkyl rings, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl,cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings ortricyclic rings, such as, for example, adamantanyl.

[0035] Cycloalkenyl is defined in each case as cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenylor cyclodecenyl, whereby the linkage can be carried out both to thedouble bond and to the single bonds.

[0036] Halogen is defined in each case as fluorine, chlorine, bromine oriodine.

[0037] Alkenyl is defined in each case as a straight-chain or branchedalkenyl radical that contains 2-6, preferably 2-4, C atoms. For example,the following radicals can be mentioned: vinyl, propen-1-yl,propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl,2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl,but-3-en-1-yl, and allyl.

[0038] The aryl radical in each case has 6-12 carbon atoms, such as, forexample, naphthyl, biphenyl and especially phenyl.

[0039] The heteroaryl radical in each case comprises 3-16 ring atoms,and instead of the carbon can contain one or more heteroatoms that arethe same or different, such as oxygen, nitrogen or sulfur, in the ring,and can be monocyclic, bicyclic, or tricyclic, and in addition in eachcase can be benzocondensed.

[0040] For example, there can be mentioned:

[0041] Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, etc., and benzo derivatives thereof, such as, e.g.,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl,indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as,e.g., quinolyl, isoquinolyl, etc.; or azocinyl, indolizinyl, purinyl,etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oroxepinyl, etc.

[0042] The aryl radical and the heteroaryl radical in each case can besubstituted in the same way or differently in 1, 2 or 3 places withhydroxy, halogen, C₁-C₄-alkoxy, with C₁-C₄-alkyl or C₁-C₄-alkyl that issubstituted in one or more places with halogen.

[0043] If an acid group is included, the physiologically compatiblesalts of organic and inorganic bases are suitable as salts, such as, forexample, the readily soluble alkali salts and alkaline-earth salts aswell as N-methyl-glucamine, dimethyl-glucamine, ethylglucamine, lysine,1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol.

[0044] If a basic group is included, the physiologically compatiblesalts of organic and inorganic acids are suitable, such as hydrochloricacid, sulfuric acid, phosphoric acid, citric acid, tartaric acid,fumaric acid, i.a.

[0045] The compounds of general formula I according to the inventionalso contain the possible tautomeric forms and comprise the E-isomers orZ-isomers, or, if a chiral center is present, also the racemates andenantiomers.

[0046] Those compounds of general formula I in which

[0047] A, B, and D, independently of one another, stand for a nitrogenor carbon atom, whereby at least one nitrogen atom is contained in thering,

[0048] E stands for aryl or hetaryl that is optionally substituted inone or more places in the same way or differently with halogen, cyano,C₁-C₆-alky, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl or with the group —OR⁵, —SR⁴,—SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴,—SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹,

[0049] G stands for a nitrogen atom or for the group —C—X,

[0050] L stands for a nitrogen atom or for the group —C—X,

[0051] M stands for a nitrogen atom or for the group —C—X,

[0052] Q stands for a nitrogen atom or for the group —C—X, whereby atmost one nitrogen atom is in the ring,

[0053] X stands for hydrogen, halogen or for C₁-C₆-alkyl, C₁-C₆-alkyloxyor C₁-C₆-carboxyalkyl that is unsubstituted or that is optionallysubstituted in one or more places with halogen,

[0054] R¹ stands for aryl or hetaryl that is optionally substituted inone or more places in the same way or differently with halogen, cyano,hydroxy, C₁-C₆-alkyloxy, C₂-C₆-alkenyl, aryl-C₁-C₆-alkyloxy, aralkyloxy,C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group ═O, —SO₂R⁴, OR⁵, —R⁵ or—PO(OR¹²)(OR¹³),

[0055] R² and R³, independently of one another, stand for hydrogen orfor C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetarylthat is optionally substituted in one or more places in the same way ordifferently with halogen, cyano, C₁-C₆-alkyl, phenyl,hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —NR⁶R⁷, —OR⁵,C₁-C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or

[0056] R² and R³ together with the nitrogen atom form a C₃-C₈ ring,which optionally can contain another nitrogen, sulfur or oxygen atom inthe ring, or can contain the group —N(R¹⁰), and which optionally can besubstituted in one or more places in the same way or differently withhalogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group—OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴,

[0057] R⁴ stands for hydroxy, C₁-C₆-alkyl, aryl, heteroaryl or for thegroup —NR²R³,

[0058] R⁵ stands for hydrogen, C₁-C₁₋₂-alkyl, halo-C₁-C₆-alkyl,C₃-C₆-cycloalkyl or halo-C₃-C₆-cycloalkyl, or for C₁-C₁₂-alkyl, which isinterrupted in one or more places with oxygen, or stands for the group—(CH₂)₂NR²R³, —CH₂CN or —CH₂CF₃,

[0059] R⁶ and R⁷, independently of one another, stand for hydrogen orC₁-C₆-alkyl, or

[0060] R⁶ and R⁷ together form a 5- to 7-membered ring, which cancontain an oxygen or sulfur atom or the group —N(R¹⁰)—,

[0061] R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl,aryl or hetaryl that is optionally substituted with halogen in one ormore places,

[0062] R⁹ stands for hydrogen, C₁-C₆-alkyl, tri-C₁-C₆-alkylsilyl, aryl,hetaryl or for the group —COR¹¹,

[0063] R¹⁰ stands for hydrogen, C₁-C₆-alkyl or aryl,

[0064] R¹¹ stands for hydrogen, C₁-C₆-alkyl or for the group —NR²R³, and

[0065] R¹² and R¹³, independently of one another, stand for hydrogen orC₁-C₆-alkyl, as well as isomers, enantiomers and salts thereof,

[0066] have proven especially effective.

[0067] Those compounds of general formula I, in which

[0068] A, B and D, independently of one another, stand for a nitrogen orcarbon atom, whereby at least one nitrogen atom is contained in thering,

[0069] E stands for aryl or hetaryl that is optionally substituted inone or more places in the same way or differently with halogen, cyano,C₁-C₆alkyl, C₁-C₆alkoxy, halo-C₁-C₆alkyl or with the group —OR⁵, —SR⁴,—SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴,—SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹,

[0070] G stands for a nitrogen atom or for the group —C—X,

[0071] L stands for a nitrogen atom or for the group —C—X,

[0072] M stands for a nitrogen atom or for the group —C—X,

[0073] Q stands for a nitrogen atom or for the group —C—X, whereby atmost one nitrogen atom is in the ring,

[0074] X stands for hydrogen or halogen,

[0075] R¹ stands for aryl or hetaryl that is optionally substituted inone or more places in the same way or differently with halogen, hydroxy,C₁-C₆-alkyloxy, aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with thegroup —SO₂R⁴, OR⁵, —R⁵ or —PO(OR¹²)(OR¹³),

[0076] R² and R³, independently of one another, stand for hydrogen orfor C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetarylthat is optionally substituted in one or more places in the same way ordifferently with halogen, cyano, C₁-C₆-alkyl, phenyl,hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —NR⁶R⁷, —OR⁵,C₁-C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or

[0077] R² and R³ together with the nitrogen atom form a C₃-C₈-ring,which optionally can contain another nitrogen, sulfur or oxygen atom inthe ring, or can contain the group —N(R¹⁰), and which optionally can besubstituted in one or more places in the same way or differently withhalogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group—OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴,

[0078] R⁴ stands for hydroxy or for the group —NR²R³,

[0079] R⁵ stands for hydrogen, C₁-C₁₂-alkyl or for C₁-C₁₂-alkyl, whichis interrupted in one or more places with oxygen or stands for the group—(CH₂)₂NR²R³, —CH₂CN or —CH₂CF₃,

[0080] R⁶ and R⁷, independently of one another, stand for hydrogen orC₁-C₆-alkyl, or

[0081] R⁶ and R⁷ together form a 5- to 7-membered ring, which cancontain an oxygen or sulfur atom or the group —N(R¹⁰)—,

[0082] R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl,aryl or hetaryl that is optionally substituted with halogen in one ormore places,

[0083] R⁹ stands for hydrogen, C₁-C₆-alkyl, tri-C₁-C₆-alkylsilyl, aryl,hetaryl or for the group —COR¹¹,

[0084] R¹⁰ stands for hydrogen, C₁-C₆-alkyl or aryl,

[0085] R¹¹ stands for hydrogen, C₁-C₆-alkyl or for the group —NR²R³, and

[0086] R¹² and R¹³, independently of one another, stand for hydrogen orC₃-C₆-alkyl, as well as isomers, enantiomers and salts thereof,

[0087] are especially effective.

[Key: oder=or]

[0088] in which T stands for hydrogen, C₁-C₆-alkyl or C₁-C₆-alkoxy,

[0089] R² and R³, independently of one another, stand for hydrogen orfor C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetarylthat is optionally substituted in one or more places in the same way ordifferently with halogen, cyano, C₁-C₆-alkyl, phenyl,hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —NR⁶R⁷—OR⁵,C₁-C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or

[0090] R² and R³, together with the nitrogen atom, form a C₃-C₈-ring,which optionally can contain another nitrogen, sulfur or oxygen atom inthe ring, or can contain the group —N(R¹⁰), and which optionally can besubstituted in one or more places in the same way or differently withhalogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group—OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴,

[0091] R⁴ stands for hydroxy or for the group —NR²R³,

[0092] R⁵ stands for hydrogen, C₁-C₁₋₂-alkyl or for C₁-C₁₂-alkyl, whichis interrupted in one or more places with oxygen, or stands for thegroup —CH₂)₂NR²R³, —CH₂CN, or —CH₂CF₃,

[0093] R⁶ and R⁷, independently of one another, stand for hydrogen orC₁-C₆-alkyl, or

[0094] R⁶ and R⁷ together form a 5- to 7-membered ring that can containan oxygen or sulfur atom,

[0095] R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl,aryl or hetaryl

[0096] Those compounds of general formula I, in which

[0097] A, B and D stand for a nitrogen or carbon atom, whereby at leastone nitrogen atom is contained in the ring,

[0098] E stands for hetaryl that is optionally substituted in one ormore places in the same way or differently with halogen, cyano,C₁₋₆alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl or with the group —OR⁵, —SR⁴,—SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴,—SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹,

[0099] G stands for the group —C—X,

[0100] L stands for the group —C—X,

[0101] M stands for the group —C—X,

[0102] Q stands for a nitrogen atom or for the group —C—X,

[0103] X stands for hydrogen or halogen,

[0104] R¹ stands for phenyl, thiophene, furan, oxazole, thiazole,imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline, orisoquinoline that is optionally substituted in one or more places in thesame way or differently with halogen, hydroxy, C₁-C₆-alkyloxy,aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —SO₂R⁴, OR⁵,—R⁵ or —PO(OR¹²)(OR¹³) or is substituted on the group

[0105]  that is optionally substituted in one or more places withhalogen, and

[0106] R⁹ stands for hydrogen, C₁-C₆-alkyl or tri-C₁-C₆-alkylsilyl, and

[0107] R¹² and R¹³, independently of one another, stand for hydrogen orC₁-C₆-alkyl, as well as isomers, enantiomers and salts thereof,

[0108] have good properties.

[0109] Those compounds of general formula I, in which

[0110] A, B and D, independently of one another, stand for a nitrogen orcarbon atom, whereby at least one nitrogen atom is contained in thering,

[0111] E stands for thienyl, pyridyl or for the group —COOR⁸, —CONR²R³,or —C≡C—R⁹,

[0112] G stands for the group —C—X,

[0113] L stands for the group —C—X,

[0114] M stands for the group —C—X,

[0115] Q stands for a nitrogen atom or for the group —C—X,

[0116] X stands for hydrogen or halogen,

[0117] R¹ stands for phenyl, thiophene, furan, oxazole, thiazole,imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline orisoquinoline that is optionally substituted in one or more places in thesame way or differently with halogen, hydroxy, C₁-C₆-alkyloxy,aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —SO₂R⁴, OR⁵,—R⁵ or —PO(OR¹²)(OR¹³) or substituted on the group

 [Key: oder=or

[0118]  in which T stands for hydrogen, C₁-C₆-alkyl or C₁-C₆-alkoxy,

[0119] R² and R³, independently of one another, stand for hydrogen orfor C₁-C₆-alkyl, C₃-C₆-cycloalkyl, phenyl or pyridyl that is optionallysubstituted in one or more places in the same way or differently withhalogen, C₁-C₆-alkyl, phenyl or with the group —NR⁶R⁷, —OR⁵ orC₁-C₆-alkyl-OR⁵, or

[0120] R² and R³ together with the nitrogen atom form a C₃-C₈-ring,which optionally can contain another nitrogen or oxygen atom in thering, and which optionally can be substituted in one or more places inthe same way or differently with C₁-C₆-alkyl,

[0121] R⁴ stands for hydroxy or for the group —NR³R³,

[0122] R⁵, R⁶ and R⁷, independently of one another, stand for hydrogenor C₁-C₆-alkyl, or

[0123] R⁶ and R⁷ together form a 5- to 7-membered ring, which cancontain an oxygen or sulfur atom,

[0124] R⁸ stands for hydrogen, C₁-C₆-alkyl or benzyl, and

[0125] R⁹ stands for hydrogen, C₁-C₆-alkyl or tri-C₁-C₆-alkylsilyl, and

[0126] R¹² and R³, independently of one another, stand for hydrogen orC—C₆-alkyl, as well as isomers and salts thereof,

[0127] have excellent properties.

[0128] The compounds according to the invention as well as theirphysiologically compatible salts prevent a tyrosine phosphorylation orstop the persistent angiogenesis and thus the growth and a propagationof tumors, whereby they are distinguished in particular by a slighterinhibition of isoforms of Cytochrome P 450 (2C9 and 2C19). Medicationusing the compounds according to the invention can therefore be done atno risk even without regard to pharmaceutical agents that areadministered at the same time and that are degraded via these isoforms.

[0129] The compounds of formula I as well as their physiologicallycompatible salts can be used as pharmaceutical agents based on theirinhibitory activity relative to the phosphorylation of the VEGFreceptor. Based on their profile of action, the compounds according tothe invention are suitable for treating diseases that are caused orpromoted by persistent angiogenesis.

[0130] Since the compounds of formula I are identified as inhibitors ofthe tyrosine kinases VEGFR-1 and VEGFR-2, they are suitable inparticular for treating those diseases that are caused or promoted bypersistent angiogenesis that is triggered via the VEGF receptor or by anincrease in vascular permeability.

[0131] The subject of this invention is also the use of the compoundsaccording to the invention as inhibitors of the tyrosine kinases VEGFR-1and VEGFR-2, or KDR and FLT.

[0132] Subjects of this invention are thus also pharmaceutical agentsfor treating tumors or use thereof.

[0133] The compounds according to the invention can be used either aloneor in a formulation as pharmaceutical agents for treating psoriasis,Kaposi's sarcoma, restenosis, such as, e.g., stent-induced restenosis,endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis,such as rheumatoid arthritis, hemangioma, angiofibroma; eye diseases,such as diabetic retinopathy, neovascular glaucoma; renal diseases, suchas glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombic microangiopathic syndrome, transplant rejections andglomerulopathy; fibrotic diseases, such as cirrhosis of the liver,mesangial cell proliferative diseases, arteriosclerosis, injuries tonerve tissue, and for inhibiting the reocclusion of vessels afterballoon catheter treatment, in vascular prosthetics or after mechanicaldevices are used to keep vessels open, such as, e.g., stents, asimmunosuppressive agents, for supporting scar-free healing, in senilekeratosis and in contact dermatitis.

[0134] In treating injuries to nerve tissue, quick scar formation on theinjury sites can be prevented with the compounds according to theinvention, i.e., scar formation is prevented from occurring before theaxons reconnect. A reconstruction of the nerve compounds was thusfacilitated.

[0135] The formation of ascites in patients can also be suppressed withthe compounds according to the invention. VEGF-induced edemas can alsobe suppressed.

[0136] Lymphangiogenesis plays an important role in lymphogenicmetastasizing (Karpanen, T. et al., Cancere Res. 2001 Mar 1, 61(5):1786-90, Veikkola, T., et al., EMBO J. 2001, Mar 15; 20 (6): 1223-31).

[0137] The compounds according to the invention now also show excellentaction as VEGFR kinase 3 inhibitors and are therefore also suitable aseffective inhibitors of lymphangiogenesis.

[0138] By a treatment with the compounds according to the invention, notonly a reduction in the size of metastases but also a reduction in thenumber of metastases is achieved.

[0139] The compounds according to the invention are also effective inthe case of diseases that are associated with excessivelymphangiogenesis and are therefore expected in thelymphangiohyperplasia and—dysplasia syndrome.

[0140] Such pharmaceutical agents, their formulations and uses, are alsosubjects of this invention.

[0141] The invention thus also relates to the use of the compounds ofgeneral formula I for the production of a pharmaceutical agent for useas or for treatment of psoriasis, Kaposi's sarcoma, restenosis, such as,e.g., stent-induced restenosis, endometriosis, Crohn's disease,Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis,hemangioma, angiofibroma; eye diseases, such as diabetic retinopathy,neovascular glaucoma; renal diseases, such as glomerulonephritis,diabetic nephropathy-, malignant nephrosclerosis, thrombicmicroangiopathic syndrome, transplant rejections and glomerulopathy;fibrotic diseases, such as cirrhosis of the liver, mesangial cellproliferative diseases, arteriosclerosis, injuries to nerve tissue, andfor inhibiting the reocclusion of vessels after balloon cathetertreatment, in vascular prosthetics or after mechanical devices are usedto keep vessels open, such as, e.g., stents, as immunosuppressiveagents, for supporting scar-free healing, in senile keratosis and incontact dermatitis.

[0142] The formation of ascites in patients can also be suppressed withthe compounds according to the invention. VEGF-induced edemas can alsobe suppressed.

[0143] To use the compounds of formula I as pharmaceutical agents, thelatter are brought into the form of a pharmaceutical preparation, whichin addition to the active ingredient for enteral or parenteraladministration contains suitable pharmaceutical, organic or inorganicinert carrier materials, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, capsules or in liquid form, for example as solutions,suspensions or emulsions. They also contain, moreover, adjuvants such aspreservatives, stabilizers, wetting agents or emulsifiers, salts forchanging osmotic pressure or buffers.

[0144] For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

[0145] As carrier systems, surface-active adjuvants such as salts ofbile acids or animal or plant phospholipids, but also mixtures thereofas well as liposomes or components thereof can also be used.

[0146] For oral administration, especially tablets, coated tablets orcapsules with talc and/or hydrocarbon vehicles or binders, such as forexample, lactose, corn starch or potato starch, are suitable. Theadministration can also be carried out in liquid form, such as, forexample, as juice, to which optionally a sweetener or, if necessary, oneor more flavoring substances, is added.

[0147] The dosage of the active ingredients can vary depending on themethod of administration, age and weight of the patient, type andseverity of the disease to be treated and similar factors. The dailydose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be givenas a single dose to be administered once or divided into 2 or more dailydoses.

[0148] The above-described formulations and forms for dispensing arealso subjects of this invention.

[0149] The production of the compounds according to the invention iscarried out according to methods that are known in the art. For example,compounds of formula I are obtained, in that a compound of generalformula II

[0150] in which A, B, D, G, L, M, Q, W and R¹ have the meanings that areindicated in general formula I and E stands for a carboxylic acid —COOH,

[0151] is reacted in a suitable solvent and a suitable organic base,with an amine of general formula III

H—NR⁸R⁹  (III),

[0152] in which R⁸ and R⁹ have the meanings that are indicated ingeneral formula I, according to processes that are known in theliterature, or if E means a nitrile group, the nitrile is saponified toform amide, or a compound of general formula IV

[0153] in which A, B, D, G, L, M, Q, W, R⁸ and R⁹ have the meanings thatare indicated in general formula I, and R^(x) means an ester or acidgroup, is converted into the corresponding amide.

[0154] The amide formation is carried out according to methods that areknown in the literature.

[0155] For amide formation, it is possible to start from a correspondingester. The ester is reacted according to J. Org. Chem. 1995, 8414 withaluminum trimethyl and the corresponding amine in solvents such astoluene at temperatures of 0° C. to the boiling point of the solvent. Ifthe molecule contains two ester groups, both are converted into the sameamide. Instead of aluminum trimethyl, sodium hexamethyldisilazide canalso be used.

[0156] For amide formation, however, all processes that are known frompeptide chemistry are also available. For example, the correspondingacid can be reacted with the amine in aprotic polar solvents, such as,for example, dimethylformamide, via an activated acid derivative,obtainable, for example, with hydroxybenzotriazole and a carbodiimide,such as, for example, diisopropylcarbodiimide, or else with preformedreagents, such as, for example, HATU (Chem. Comm. 1994, 201) or BTU, attemperatures of between 0° C. and the boiling point of the solvent,preferably at 80° C. For the amide formation, the process can also beused with the mixed acid anhydride, imidazolide or azide.

[0157] Nitriles can also be saponified to form amides according toprocesses that are known in the literature. The reaction with potassiumcarbonate and hydrogen peroxide is very effective in an aprotic polarsolvent such as dimethyl sulfoxide, preferably at room temperatureaccording to Synthesis, 1989, 949.

[0158] In addition, the compounds of general formula I according to theinvention can be produced in that a compound of general formula IIa

[0159] in which A, B, D, G, L, M, Q, W and R¹ have the meanings that areindicated in general formula I, and E means a halogen or an O-sulfonate,such as, e.g., a chlorine, bromine or iodine atom, anO-trifluoromethanesulfonate or O-methylsulfonate,

[0160] a. is reacted with appropriately substituted terminal alkenes ina Heck reaction (cf. “Palladium Reagents in Organic Syntheses,” AcademicPress 1985, New York, pp. 179 ff.) or with vinylboronic acids orvinylboronic acid esters in a Suzuki reaction (cf. Tetrahedron Lett.1983, 39, 3271 ff.) or with vinyl stannanes in a Stille reaction (cf.Pure & Appl. Chem. 1985, 57, 1771), or

[0161] b. is coupled with any substituted terminal alkines, for example,according to the method of Stephens-Castro (cf. J. Org. Chem. 1963, 28,3313 ff.) or palladium-catalyzed according to the method of Sonogashira(cf. “Comprehensive Organic Synthesis: Carbon-Carbon σ-Bond Formation,”Pergamon Press 1991, Oxford UK, Volume 3, pp. 551ff.), or

[0162] c. is coupled with aryl and hetaryl boronic acids or their estersin a Suzuki reaction (cf. Acc. Chem. Res. 1991, 63, 419 ff. or J. Am.Chem. Soc. 2000, 122, 4020 ff.) or with aryl and hetaryl stannanes in aStille reaction (cf. Angew. Chem. 1986, 98, 504 ff. or Angew. Chem. Int.Ed. 1999, 38, 2411 ff.) or with aryl and hetaryl Grignard compounds orthe analogous zinc-organic derivatives in a Negishi reaction (cf.“Metal-Catalyzed Cross-Coupling Reaction,” Eds. Diederich/Stang,Wiley-VCH 1998, New York, Chapter 1 or else J. Am. Chem. Soc. 2001, 123,2719 ff.), or

[0163] d. is converted in a palladium-catalyzed carbonylation under 1 to20 bar of carbon monoxide atmosphere in dimethylformamide in thepresence of the corresponding alcohol (cf. “Palladium Reagents inOrganic Syntheses,” Academic Press 1985, New York, pp. 352 ff. or Synth.Comm. 1997, 27, 515 ff.) into the corresponding carboxylic acid ester,or

[0164] e. is converted in a palladium-catalyzed carbonylation under 1 to20 bar of carbon monoxide atmosphere in dimethylformamide-water mixturesinto the corresponding carboxylic acid (cf. J. Org. Chem. 1981, 46, 4614ff.). The carboxylic acids can also be obtained by saponification of thecarboxylic acid esters, or

[0165] f. the corresponding carboxylic acid amides are produced in apalladium-catalyzed carbonylation under 1 to 20 bar of carbon monoxideatmosphere in dimethylformamide in the presence of amines (cf.“Palladium Reagents in Organic Syntheses,” Academic Press 1985, NewYork, pp. 352 ff., Tetrahedron Lett. 1982, 23, 3383 ff.). The synthesisof the carboxylic acid amides can also be carried out from carboxylicacid esters; the method according to Weinreb has especially proven itsvalue here (cf. Tetrahedron Lett. 1977, 17, 4171 ff., J. Org. Chem.1995, 60, 8414 ff.). The carboxylic acid amides can also be synthesizedfrom the carboxylic acids that are produced under e); basically allprocesses that are known from the peptide chemistry are available forthis purpose (cf. Synthesis 1972, 453-63 or “Comprehensive OrganicTransformations,” Wiley-VCH 1989, New York, 972-6). For example, thecorresponding carboxylic acid in aprotic polar solvents, such as, forexample dimethylformamide, can be reacted with an activated carboxylicacid derivative, produced, for example, by adding carbonyldiimidazole,at temperatures of between 0-120° C., preferably at room temperature,with amines, such as, for example HATU (Chem. Comm. 1994, 201), or

[0166] g. the corresponding sulfide is converted with thioalkylene,thioarylene and thiohetarylene directly, in the presence of bases, suchas, for example, potassium hydride or potassium tert-butanolate ortransition metals, such as, for example, copper chips, copper chlorideor copper bromide or palladium dichloride in aprotic solvents, such as,for example, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxideor xylene at temperatures of between 20-200° C. The execution of thereaction in a microwave device can turn out to be advantageous in thiscase (cf. Tetrahedron 1983, 39, 4153 ff.). The production of2-thio-substituted pyridyl derivatives can also be carried out easilyfrom the 2-pyridone derivative after thionylation with phosphoruspentasulfide (cf. Bull. Soc. Chim. Fr.; 1953; 1001 ff.) or Lawesson 'sreagent (Tetrahedron 1984, 40, 2047 ff.) and subsequent alkylation withalkyl halides, preferably with alkyl iodides (cf. J. Org. Chem. 1999;64, 7935-9) or alkyl sulfonates, preferablyalkyltrifluoromethylsulfonates.

[0167] h. The corresponding sulfoxides can be obtained by oxidation ofsulfides with standard oxidizing agents, such as, for example, hydrogenperoxide, sodium periodate, tert-butoxy hypochlorite, sodium chlorite,metachloroperbenzoic acid, trifluoroperoxyacetic acid, dimethyldioxiram, cerium ammonium nitrate or nitric acid (cf. “Oxidations inOrganic Chemistry,” ACS Washington 1990, pp. 252-63) in solvents, suchas, for example, dichloromethane, dichloroethane, chloroform,tetrahydrofuran, acetonitrile, dimethylformamide, N-methylpyrrolidinone,dimethyl sulfoxide, dimethoxyethane, diglyme, tetraglyme or water, attemperatures of between 20° C. and the boiling point of the solvent. Thethus obtained sulfoxides can further be oxidized to the correspondingsulfones; the latter is achieved, for example, by oxidizing agents suchas hydrogen peroxide, potassium permanganate, sodium perborate orpotassium hydrogen persulfate (cf. Tetrahedron Lett. 1981, 22, 1287 ff.)in solvents, such as, for example, dichloromethane, dichloroethane,chloroform, tetrahydrofuran, acetonitrile, dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide or water, at temperatures ofbetween 20° C. and the boiling point of the solvent. The treatment ofsulfides with an excess of the above-cited oxidizing agents resultsdirectly in the corresponding sulfones (cf. “The Chemistry of Sulphonesand Sulfoxides” in Patai, Wiley 1988, New York, pp. 165-231).

[0168] i. By oxidation of the thiols that are obtained under g), thechlorosulfonates can be produced; the oxidation with chlorine in aqueoushydrochloric acid (cf. J. Org. Chem. 1999; 64, 5896-903) or carbontetrachloride (cf. J. Med. Chem. 2000, 43, 843-58) or with sodiumhypochlorite in sulfuric acid (cf. Tetrahedron Asymm. 1997; 8; 3559-62)has especially proven its value here.

[0169] j. By reaction with a mixture that consists of copper rhodanideand potassium rhodanide in polar aprotic solvents, such as, for example,acetonitrile, dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, diglyme, tetraglyme, N-methylpyrrolidinone, the correspondingthiocyanates can be obtained (cf. J. Chem. Soc. Chem. Comm. 1989, 81ff). From the latter in turn, the corresponding sulfonic acid chloridescan be obtained by oxidation with hypochlorite.

[0170] k. By reaction of the chlorosulfonates that are cited under i)with amines, in solvents, such as, for example, dichloromethane,dichloroethane, chloroform, tetrahydrofuran, ethyl acetate,acetonitrile, dimethylformamide, N-methyl-pyrrolidone,N,N-dimethylacetamide, dimethoxyethane or water, at temperatures ofbetween 0° C. and the boiling point of the solvent, the correspondingsulfonamides can be obtained (cf. Tetrahedron 2000, 56, 8253-62).

[0171] l. By hydrolysis of the chlorosulfonates that are obtained underi) in water or aqueous alkaline solution at temperatures of between 5°C. and 100° C., the corresponding sulfonic acids are obtained.

[0172] m. By palladium-catalyzed reaction with O,O-dialkylphosphites inaprotic solvents, such as, for example, dimethylformamide,N-methyl-pyrrolidinone, N,N-dimethylacetamide, dimethyl sulfoxide ortoluene in the presence of a base, such as, for example, triethylamineor diisopropylethylamine, at temperatures of between 0° C. and theboiling temperature of the solvent, preferably at 80° C., thecorresponding phosphonates can be obtained (cf. Bull. Chem. Soc. Jpn.1982, 55, 909 ff.).

[0173] n. By metallation, for example with n-butyllithium,sec-butyllithium, tert-butyllithium, methyllithium, lithiumdiisopropylamide or ethyl magnesium bromide, in aprotic solvents suchas, for example, diethyl ether, tetrahydrofuran or dioxane, attemperatures of between −100° C. and 0° C., preferably at −78° C. intetrahydrofuran and reaction with isocyanates, the correspondingcarboxylic acid amides can be obtained.

[0174] o. By having the reaction carried out analogously to what isdescribed under n) and having the recovery of the metallatedintermediate stages be done with chloroformic acid ester, thecorresponding carboxylic acid esters can be obtained.

[0175] p. By having the reaction carried out analogously to what isdescribed under n) and having the recovery of the metallatedintermediate stages be done with dimethylformamide, ethyl formate orN-formylmorpholine, the corresponding aldehydes can be obtained.

[0176] q. By having the reaction carried out analogously to what isdescribed under n) and having the recovery of the metallatedintermediate stages be done with alkyl halides or alkyl sulfonates,preferably alkyl iodides or alkyltrifluoromethanesulfonates, thecorresponding pyridylalkyl derivatives can be produced.

[0177] r. By reduction with hydrogen in the presence of catalyticamounts of palladium, nickel or rhodium metal or salts of these metals,for example palladium on activated carbon in polar-protic solvents orsolvent mixtures, such as, for example, methanol-glacial acetic acid,the pyridylalkenes that are produced under a) and the pyridylalkinesthat are produced under b) are converted into the correspondingpyridylalkanes.

[0178] The sequence of the process steps can also be interchanged in allcases.

[0179] Production of the Compounds According to the Invention

[0180] The following examples explain the production of the compoundsaccording to the invention without the scope of the claimed compoundsbeing limited to these examples.

EXAMPLE 1

[0181] Production of5-{[2-(Isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicacid propylamide

[0182] 50 mg (0.13 mmol) of5-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicacid and 42 mg (0.26 mmol) of carbonyldiimidazole are introduced into2.5 ml of dimethylformamide under argon and in a moisture-freeenvironment, and it is stirred for 30 minutes at room temperature. 15 mg(0.26 mmol) of n-propylamine is then added to the batch, and stirring iscontinued for 12 hours at room temperature. It is then diluted withwater to about 30 ml and shaken out three times with 20 ml of ethylacetate each. The collected organic phase is dried, filtered andconcentrated by evaporation, and the residue is chromatographed on aFlash column (5 g; Isolute flash silica, Separtis Company) with agradient of 100% hexane to 50% hexane and 50% ethyl acetate. 45 mg (79%of theory) of5-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicacid propylamide with a molar peak in MS m/e=439 is obtained.

[0183] Similarly produced are also the following compounds:

Smp. [° C.]/MS Beispiel Nr. A B D R² R³ MW Molpeak (m/e) 1.1 C C N —CH₃—CH₃ 425.49 1.2 C C N —CH(CH₃)₂ H 439.52 Harz/439 1.3 C C N

H 437.50 Harz/437 1.4 C C N —CH₂CF₃ H 1.5 C C N —(CH₂)₂-OH H 441.49Harz/441 1.6 C C N —(CH₂)₃OH H 455.52 Harz/455 1.7 C C N —(CH₂)₄OH H469.54 Harz/469 1.8 C C N

H 455.52  155 1.9 C C N

H 455.52 Harz/455 1.10 C C N

H 455.52  109 1.11 C C N

H 455.52   82 1.12 C C N

H 483.87 Harz/483 1.13 C C N —(CH₂)₂N(CH₃)₂ H 468.  /468 1.14 C C N—(CH₂)₃N(CH₃)₂ H 482.59 /469

[0184]

Smp. [° C.]/MS Beispiel Nr. A B D R² R³ MW Molpeak (m/e) 1.15 C N C —CH₃—CH₃ 425.49 106 1.16 C N C —CH₃ H 411.46 180 1.17 C N C —C₂H₅ H 425.49165 1.18 C N C

H 437.50 172 1.19 C N C —(CH₂)₂—OH H 441.49 136 1.20 C N C

H 474.52 207 1.21 C N C

H 465.55 94 1.22 C N C

H 473.53 187 1.23 C N C —C₃H₇ H 439.52 96 1.24 C N C —CH(CH₃)₂ H 439.52174 1.25 C N C

H 455.52 103 1.26 C N C

H 455.52 110 1.27 C N C

H 455.52 105 1.28 C N C

H 455.52 100 1.29 C N C

H 479.58 110 1.30 C N C

H 491.52 204 1.31 C N C

H 487.56 151 1.32 C N C —(CH₂)₃—OH H 455.52 65 1.33 C N C —(CH₂)₅—OH H483.57 70 1.34 C N C —(CH₂)₄—OH H 469.54 70 1.35 C N C —(CH₂)₂N(CH₃)₂ H455.52 98 1.36 C N C —(CH₂)₃N(CH₃)₂ H 482.59 95 1.37 C N C

H 503.56 190 1.38 C N C

H 474.52 190 1.39 C N C

H 474.52 105 1.40 C N C

H 483.57 75 1.41 C N C

H 469.54 50 1.42 C N C

H 469.54 170 1.43 C N C —(CH₂)₂OCH₃ H 455.52 67 1.44 C N C

H 483.57 86 1.45 C N C

H 497.6  86 1.46 C N C

H 483.57 66 1.47 C N C

H 495.58 148 1.48 C N C

H 517.58 78 1.49 C N C

H 517.58 91 1.50 C N C

H 471.51 85 1.51 C N C

H 497.59 98 1.52 C N C CH₂CF₃ H 479.46 96 1.53 C N C

H 495.58 127 1.54 C N C

H 497.59 96 1.55 C N C

H 469.54 78 1.56 C N C

H 469.54 78 1.57 C N C

H 510.59 1.58 C N C

H 524.62 1.59 C N C

H 469.54

[0185]

Smp. [° C.] oder MS Beispiel Molpeak Nr. A D B R² R³ MW (m/e) 1.60 C C N—CH(CH₂OH)₂ H 488,46 97 1.61 C C N —(CH₂)₃OH H 500.52 125 1.62 C C N—(CH₂)₂—OMe H 472.46 67 1.63 C C N —(CH₂)₅OH H 500.52 92 1.64 C C N—(CH₂)₄OH H 486.49 73 1.65 C C N

H 472.46 82 1.66 C C N

H 472.46 73 1.67 C C N

H 472.46 87 1.68 C C N

H 472.46 93 1.69 C C N

H 486.49 67 1.70 C C N

H 500.52 67 1.71 C C N —(CH₂)₂N(CH₃)₂ H 485.51 82 1.72 C C N—(CH₂)₂N(CH₃)₂ H 499.53 74 1.73 C C N

H 491.47 142 1.74 C C N

H 491.47 104 1.75 C C N

H 491.47 73

[0186]

Beispiel Smp. [° C.]/MS Nr. A B D Z MW Molpeak (m/e) 1.76 C N C —CH₃480.57 99

[0187]

Smp. [° C.]/ Beispiel MS Molpeak Nr. A B D R² R³ MW (m/e) 1.77 C N C

H 473.50 1.78 C N C

H 473.50 1.79 C N C

H 473.50 1.80 C N C

H 473.50 1.81 C N C —(CH₂)₂N(CH₃)₂ H 486.54

[0188]

Smp. [° C.] oder MS Beispiel Molpeak Nr. A B D R² R³ MW (m/e) 1.82 C C N—(CH₂)₃OH H 500,52 80 1.83 C C N

H 472.46 50 1.84 C C N

H 472.46 83 1.85 C C N

H 472.46 129 1.86 C C N

H 491.47 150 1.87 C C N

H 491.47 148 1.88 C C N —(CH₂)₅OH H 500.52 101 1.89 C C N —CH(CH₂OH)₂ H488.46 144 1.90 C C N —(CH₂)₃N(CH₃)₂ H 499.53 117 1.91 C C N —(CH₂)₂—OMeH 472.46 54 1.92 C C N

H 491.47 121 1.93 C C N —(CH₂)₂N(CH₃)₂ H 485.51 139 1.94 C C N

H 500.52 70 1.95 C C N

H 486.49 88 1.96 C C N

H 472.46 76 1.97 C C N —(CH)₄OH H 488.52

[0189]

Smp. [° C.]/ Beispiel MS Molpeak Nr. A B D R¹ R² R³ MW (m/e) 1.98  C N C

H 459.50 1.99  C N C

H 458.51 1.100 C N C

H 458.51 1.101 C N C

H 444.49 1.102 C N C

H 444.49 1.103 C N C

H 458.51 1.104 C N C

H 458.51 1.105 C N C

H 444.49 1.106 C N C

H 444.49

[0190]

Smp. [° C.]/ Beispiel MS Molpeak Nr. A D B R¹ R² R³ MW (m/e) 1.107 C N C

H 459.50 160.7 1.108 C N C

H 459.50 123.8 1.109 C N C

H 459.50 123   1.110 C N C

H 459.50 1.111 C N C

H 502.52 199.2 1.112 C N C

H 502.52 180.4 1.113 C N C

H 502.52 1.114 C N C

H 499.56 1.115 C N C

H 499.56 174   1.116 C N C

H 499.56 173.8 1.117 C N C

H 458.51 1.118 C N C

H 458.51 1.119 C N C

H 458.51 1.120 C N C

H 458.51 1.121 C N C

H 444.49 1.122 C N C

H 444.49 1.123 C N C

H 444.49 1.124 C N C

H 444.49 1.125 C N C

H 502.52

EXAMPLE 2.0

[0191] Production of5-{[2-(Isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Pyridin-3-ylamide

[0192] 120 mg (0.3 mmol) of5-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicacid is dissolved under argon in 5 ml of absolute dimethylformamide,mixed with 56 mg (0.6 mmol) of 3-aminopyridine, 76 mg (0.75 mmol) ofN-methylmorpholine and 136 mg (0.36 mmol) ofO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) and stirred for 48 hours at room temperature.Then, it is concentrated by evaporation in a vacuum, and the residue ischromatographed on a flash column (5 g of Isolute flash silica, SepostisCompany) with a gradient of methylene chloride: ethanol=100:0 to 95:5 asan eluant. Mgof5-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicacid pyridin-3-ylamide is obtained.

[0193] MS (m/e 474)

[0194] Similarly produced are:

Smp. [° C.]/ Beispiel MS Molpeak Nr. A B D R² R³ MW (m/e) 2.1 C C N

H 474.52 474 (m/e) 2.2 C C N

H 474.52 474 (m/e)

EXAMPLE 3.0

[0195] Production of5-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

[0196] 36 mg (0.09 mmol) of2-[(6-cyano-pyridin-3-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamideis mixed in 1 ml of dimethyl sulfoxide with 30 mg (0.22 mmol) ofpotassium carbonate and 0.05 ml (0.42 mmol) of hydrogen peroxide (30%),and it is stirred for 3.5 hours at room temperature. It is then dilutedwith water and extracted with ethyl acetate. The organic phase iswashed, dried, filtered and concentrated by evaporation. The residue isabsorptively precipitated with warm methanol. 5 mg (11% of theory) of5-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicacid amide is obtained.

[0197] Similarly produced are:

EXAMPLE 3.1

[0198]4-{[2-(7-Methoxy-3-methyl-quinolin-2-ylcarbamoyl)-phenylamino]-methyl-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.2

[0199]4-12-(7-Methoxy-2-oxo-2H-chromen-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.3

[0200]5-{[2-(7-Methoxy-2-oxo-2H-chromen-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.4

[0201]5-{[2-(7-Methoxy-3-methyl-quinolin-2-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.5

[0202]4-{[2-(Isoquinolin-3-ylcarbamoyl)-6-azaphenylamino]-methyl}-pyridine-2-carboxyticAcid Amide

EXAMPLE 3.6

[0203]5-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.7

[0204]4-{[2-(2-Methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.8

[0205]4-{[2-(1H-Indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.9

[0206]4-{[2-(1-Methyl-1H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.10

[0207]5-{[2-(Isoquinolin-3-ylcarbamoyl)-6-azaphenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

EXAMPLE 3.11

[0208]4-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid Amide)

EXAMPLE 4.0

[0209] Production ofN-tert-Butyl-(4-{[2-(isoquinolin-3-ylcarbamoyl)-6-azaphenylamino]-methyl}-pyridine-2-carboxylicAcid Amide

[0210] In 5 ml of toluene, 72 mg (0.5 mmol) of 3-aminoisoquinoline ismixed with 0.25 ml of trimethylaluminum (0.5 mmol; 2 mol in toluene)under a cover gas and in a moisture-free environment, and it is stirredfor 30 minutes at room temperature. 120 mg (0.45 mmol) of2-[(2-tert-butylcarbamoyl-pyridin-4-ylmethyl)-amino]-nicotinic acidmethyl ester is then added, and it is heated for 2 hours to 120° C.After cooling, it is mixed with 30 ml of dilute sodium bicarbonatesolution and extracted three times with 30 ml of ethyl acetate each. Thecollected ethyl acetate phase is washed with water, dried, filtered andconcentrated by evaporation. The residue is chromatographed on silicagel with methylene chloride:ethanol=95:5 as an eluant. After a secondchromatography on silica gel with hexane:ethyl acetate=1:1 as an eluant,70 mg (30% of theory) ofN-tert-butyl-(4-{[2-(isoquinolin-3-ylcarbamoyl)-6-azaphenylamino]-methyl}-pyridine-2-carboxylicacid amide) with a melting point of 20¹° C. is obtained.

EXAMPLE 5.0

[0211] Production of4-{[2-(Isoquinolin-3-ylcarbamoyl)-6-azaphenylamino]-methyl}-pyridine-2-carboxylicAcid (2-Hydroxy-propyl)-amide

[0212] 283 mg (1 mmol) of 2-chloro-N-isoquinolin-3-yl-nicotinamide ismixed in 5 ml of pyridine with about 1.66 mmol of4-aminomethyl-pyridine-2-carboxylic acid (2-hydroxy-propyl)-amide, andit is heated for 2 hours to 100° C. After concentration by evaporation,it is taken up in water and shaken out three times with 30 ml of ethylacetate each. The collected organic phase is washed with water, dried,filtered and concentrated by evaporation. The residue is chromatographedon silica gel with methylene chloride:acetone 1:1 as an eluant. 40 mg(9% of theory) of4-{[2-(isoquinolin-3-ylcarbamoyl)-6-azaphenylamino]-methyl}-pyridine-2-carboxylicacid (2-hydroxy-propyl)-amide is obtained as a resin.

EXAMPLE 6.0

[0213] Production ofN-(Isoquinolin-3-yl)-2-[3-(pyridin-3-yl)-pyridin-4-yl-methylamino]-benzoicAcid Amide

[0214] 94 mg (0.22 mmol) ofN-(isoquinolin-3-yl)-2-[3-bromopyridin-4-yl-methylamino]-benzoic acidamide is mixed in 3.7 ml of toluene in succession with 0.73 ml ofethanol, 0.36 ml of a 2 mol sodium carbonate solution, 6 mg ofpalladium(0)tetrakistriphenylphosphine and 32 mg of pyridine-3-boronicacid, and it is heated for 6.5 hours to a bath temperature of 120° C. Itis then diluted with water to 25 ml and extracted three times with 25 mlof ethyl acetate each. The collected ethyl acetate phase is dried,filtered and concentrated by evaporation. The residue is chromatographedon silica gel with methylene chloride, ethanol=10:1 as an eluant. 45 mg(47% of theory) ofN-(isoquinolin-3-yl)-2-[3-(pyridin-3-yl)-pyridin-4-yl-methylamino]-benzoicacid amide is obtained as a resin.

[0215]¹H-NMR (d6-DMSO): 10.68 (s, 1H), 9.21 (s, 1H), 8.72 (s, 1H), 8.64(d, J=3.8, 1H), 8.57 (d, J=5.1, 1H), 8.54 (s, 1H), 8.48 (s, 1H),8.11-7.94 (m, 4H), 7.85 (d, J=7.6, 1H), 7.74 (t, J=7.3, 1H), 7.59-7.47(m, 3H), 7.23 (t, J=7.5, 1H), 6.63 (t, J=7.5, 1H), 6.39 (d, J=8.3, 1H),4.45 (d, J=5.0, 2H).

[0216] MS (CI—NH3): 432 (80%, [M+H]⁺)

EXAMPLE 6.1

[0217] Production ofN-(Isoquinolin-3-yl)-2-[3-(thien-3-yl)-pyridin-4-yl-methylamino]-benzoicAcid Amide

[0218] Similarly produced is alsoN-(isoquinolin-3-yl)-2-[3-(thien-3-yl)-pyridin-4-yl-methylamino]-benzoicacid amide:

[0219] MS (CI—NH3): 437 (100%, [M+H]⁺)

EXAMPLE 6.2

[0220] Production ofN-(Isoquinolin-3-yl)-2-[2-amino-carbonylpyridin-4-yl-methylamino]-benzoicAcid Amide

[0221] 130 mg (0.34 mmol) ofN-(isoquinolin-3-yl)-2-[2-cyanopyridin-4-yl-methylamino]-benzoic acidamide is mixed in 2.5 ml of dimethyl sulfoxide with 126 mg of potassiumcarbonate and 0.25 ml of hydrogen peroxide (30%), and it is stirred for1 hour at room temperature. It is then mixed with water, and theprecipitated product is suctioned off. The residue is absorptivelyprecipitated in a mixture that consists of methylene chloride/ethanoland suctioned off. 96 mg (71% of theory) ofN-(isoquinolin-3-yl)-2-[(2-aminocarbonylpyridin-4-yl)-methylamino]-benzoicacid amide with a melting point of 200° C. is obtained.

[0222]¹H-NMR (d6-DMSO): 10.73 (s, 1H), 9.22 (s, 1H), 8.60 (s, 1H), 8.56(d, J=4.7, 1H), 8.25 (br.s, 1H), 8.10-8.04 (m, 3H), 7.95 (d, J=8.0, 1H),7.88 (d, J=6.9, 1H), 7.74 (t, J=7.4, 1H), 7.63-7.57 (m, 3H), 7.25 (t,J=7.0, 1H), 6.64 (t, J=7.5, 1H), 6.54 (d, J=8.4, 1H), 4.62 (br.d, J=5.5,2H).

[0223] MS (EI): 397 (38%, [M]⁺)

EXAMPLE 6.3

[0224] Production ofN-(Isoquinolin-3-yl)-2-[(2-aminocarbonylpyridin-5-yl)-methylamino]-benzoicAcid Amide

[0225] Similarly produced is alsoN-(isoquinolin-3-yl)-2-[(2-aminocarbonylpyridin-5-yl)-methylamino]-benzoicacid amide

[0226] MS (ESI): 398 (78%, [M+H]⁺)

EXAMPLE 6.4

[0227] Production ofN-(Isoquinolin-3-yl)-2-[(2-methoxycarbonylpyridin-4-yl)-methylamino]-benzoicAcid Amide

[0228] 20 mg ofN-(isoquinolin-3-yl)-2-[2-bromopyridin-4-yl-methylamino]-benzoic acidamide (0.05 mmol), 1.6 mg (0.003 mmol) ofbis(diphenylphosphine)ferrocene (DPPF), 0.35 mg (0.0015 mmol) ofpalladium(II) acetate, and 14 μl (0.1 mmol) of triethylamine aresuspended in a mixture that consists of 1 ml of methanol and 1 ml ofdimethylformamide, and it is stirred for 5 hours in an autoclave underCO atmosphere (3 bar) at 50° C. The reaction mixture is filtered using amembrane filter, concentrated by evaporation and chromatographed onsilica gel with hexane: EtOAc=3:7 as an eluant. 12 mg (58% of theory) ofN-(isoquinolin-3-yl)-2-[(2-methoxycarbonylpyridin-4-yl)-methylamino]-benzoicacid amide is obtained.

[0229]¹H-NMR (CDCl₃): 9.12 (br.s, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.61(d, J=5.1, 1H), 8.36 (br.s, 1H), 8.09 (s, 1H), 7.87 (d, J=8.5, 1H), 7.81(d, J=8.5, 1H), 7.71 (d, J=7.7, 1H), 7.64 (t, J=7.8, 1H), 7.49-7.44 (m,2H), 7.24-7.19 (m, 1H), 6.68 (t, J=7.8, 1H), 6.42 (d, J=8.0, 1H), 4.50(br.s, 2H), 3.93 (s, 3H).

[0230] MS (ESI): 413 (100%, [M+H]⁺)

EXAMPLE 6.5

[0231] Production ofN-(Isoquinolin-3-yl)-2-[(2-benzyloxycarbonylpyridin-4-yl)-methylamino]-benzoicAcid Amide

[0232] Similarly produced is alsoN-(isoquinolin-3-yl)-2-[(2-benzyloxycarbonylpyridin-4-yl)-methylamino]-benzoicacid amide.

[0233]¹H-NMR (CDCl₃): 9.00 (s, 1H), 8.76 (br.s, 1H), 8.68 (d, J=5.0,1H), 8.66 (s, 1H), 8.39 (t, J=6.1, 1H), 8.14 (s, 1H), 7.91 (d, J=7.9,1H), 7.85 (d, J=8.0, 11H), 7.69-7.62 (m, 2H), 7.53-7.46 (m, 4H),7.38-7.25 (m, 4H), 6.73 (t, J=7.2, 1H), 6.48 (d, J=7.8, 1H), 5.44 (s,2H), 4.56 (d, J=6.0, 2H).

[0234] MS (CI—NH3): 489 (85%, [M+H]⁺)

EXAMPLE 6.6

[0235] Production ofN-(Isoquinolin-3-yl)-2-[(2-hydroxycarbonylpyridin-4-yl)-methylamino]-benzoicAcid Amide

[0236] a. 20 mg ofN-(isoquinolin-3-yl)-2-[(2-methoxycarbonylpyridin-4-yl)-methylamino]-benzoicacid amide (0.05 mmol) is mixed in a mixture that consists of 1 ml oftetrahydrofuran and 1 ml of methanol with 10.2 mg (0.25 mmol) of lithiumhydroxide in water, and it is stirred for 4 hours at 22° C. The reactionmixture is filtered using a membrane filter, concentrated by evaporationand chromatographed on silica gel with toluene:acetic acid:water 10:10:1as an eluant. 14 mg (69% of theory) ofN-(isoquinolin-3-yl)-2-[(2-hydroxy-carbonylpyridin-4-yl)-methylamino]-benzoicacid amide is obtained.

[0237] b. 433 mg ofN-(isoquinolin-3-yl)-2-[2-bromopyridin-4-yl)-methylamino]-benzoic acidamide (1 mmol), 50 mg (0.09 mmol) of bis(diphenylphosphine)ferrocene(DPPF), 10 mg (0.045 mmol) of palladium(II) acetate, and 280 μl (2 mmol)of triethylamine are suspended in a mixture that consists of 5 ml ofwater and 10 ml of dimethylformamide, and it is stirred for 5 hours inan autoclave under CO atmosphere (3 bar) at 50° C. The reaction mixtureis filtered using a membrane filter, concentrated by evaporation,dissolved in dichloromethane, mixed with activated carbon, heated,filtered and concentrated by evaporation. The solid that is obtained isrecrystallized from dichloromethane. 283 mg (71% of theory) ofN-(isoquinolin-3-yl)-2-[(2-hydroxycarbonylpyridin-4-yl)-methylamino]-benzoicacid amide is obtained.

[0238]¹H-NMR (d6-DMSO): 10.73 (s, 1H), 9.22 (s, 1H), 8.63 (d, J=4.9,1H), 8.60 (s, 1H), 8.22 (br.t, J=6.0, 1H), 8.10 (d, J=8.0, 1H), 8.04 (s,1H), 7.94 (d, J=8.1, 1H), 7.87 (d, J=6.8, 1H), 7.74 (t, J=7.5, 1H),7.60-7.54 (m, 2H), 7.25 (t, J=7.0, 1H), 6.65 (t, J=7.6, 1H), 6.54 (d,J=8.4, 1H), 4.62 (br.d, J=5.5, 2H). A proton is not observed or ismasked.

[0239] MS(CI—NH3): 399 (75%, [M+H]⁺)

[0240] Melting point: 185° C.

EXAMPLE 6.7

[0241] Production ofN-(isoquinolin-3-yl)-2-[(2-morpholinocarbonylpyridin-4-yl)-methylamino]-benzoicAcid Amide

[0242] A mixture that consists of 40 mg ofN-(isoquinolin-3-yl)-2-[(2-hydroxycarbonylpyridin-4-yl)-methylamino]-benzoicacid amide (0.1 mmol) and 9 μl (0.1 mmol) of morpholine in 1 ml ofdimethylformamide is mixed in portions with 34 mg (0.2 mmol) ofcarbonyldiimidazole. After 4 hours of stirring at 22° C., it isconcentrated by evaporation, the residue is dissolved in 5 ml ofdichloromethane, washed with 1 mol of aqueous potassium carbonatesolution (2 ml), dried (MgSO₄), filtered and concentrated byevaporation. Colorless resin (38 mg, 81% of theory).

[0243]¹H-NMR (CDCl₃): 9.02 (s, 1H), 8.71 (br.s, 1H), 8.64 (s, 1H), 8.51(d, J=5.1, 1H), 8.36 (t, J=6.0, 1H), 8.01 (s, 1H), 7.93-7.82 (m, 2H),7.69-7.64 (m, 2H), 7.50 (t, J=7.8, 1H), 7.39 (d, J=6.1, 1H), 7.28-7.20(m, 1H), 6.73 (t, J=7.8, 1H), 6.52 (d, J=8.1, 1H), 4.55 (d, J=6.0, 2H),3.79-3.62 (m, 8H).

[0244] MS (EI): 467 (15%, [M+H]⁺)

EXAMPLE 6.8

[0245] Production ofN-(Isoquinolin-3-yl)-2-[3-trimethylsilylethinylpyridin-4-yl)-methylamino]-benzoicAcid Amide

[0246] 108 mg (0.25 mmol) ofN-(isoquinolin-3-yl)-2-[3-bromopyridin-4-yl)-methylamino]-benzoic acidamide is mixed in 1 ml of dimethylformamide with 1 ml of triethylamine,5 mg (0.026 mmol) of copper-1-iodide, 9 mg (0.008 mmol) of palladiumtetrakis triphenylphosphine and 0.07 ml of trimethylsilylacetylene, andit is heated under argon and in a moisture-free environment for 3.5hours to a bath temperature of 70° C. It is then mixed with 40 ml ofwater and extracted three times with 25 ml of ethyl acetate each. Theethyl acetate phase is washed with water, dried, filtered andconcentrated by evaporation. The residue is chromatographed on silicagel with ethyl acetate:hexane=1:1 as an eluant. 38 mg (33.6% of theory)ofN-(isoquinolin-3-yl)-2-[3-trimethylsilyl-ethinylpyridin-4-yl)-methylamino]-benzoicacid amide is obtained as an amorphous solid.

[0247]¹H-NMR (d6-DMSO): 10.71 (s, 1H), 9.22 (s, 1H), 8.62 (s, 1H), 8.58(s, 1H), 8.49 (d, J=4.9, 1H), 8.21 (br.t, J=6.1, 1H), 8.09 (d, J=8.2,1H), 7.92 (d, J=8.0, 1H), 7.88 (d, J=7.9, 1H), 7.74 (t, J=8.0, 1H), 7.57(t, J=7.7, 1H), 7.40 (d, J=5.1, 1H), 7.28 (t, J=7.5, 1H), 6.65 (t,J=7.7, 1H), 6.54 (d, J=8.1, 1H), 4.58 (d, J=6.0, 2H), 0.27 (s, 3H).

[0248] MS (EI): 450 (105%, [M]⁺)

EXAMPLE 6.9

[0249] Production ofN-(Isoquinolin-3-yl)-2-[2-trimethylsilylethinylpyridin-4-yl)-methylamino]-benzoicAcid Amide

[0250] Produced in a way similar to Example 9 is alsoN-(isoquinolin-3-yl)-2-[2-trimethylsilylethinylpyridin-4-yl)-methylamino]-benzoicacid amide

[0251] Production of Starting and Intermediate Compounds

[0252] If the production of the intermediate compounds is not described,the latter are known or can be produced analogously to known compoundsor processes that are described here.

EXAMPLE A

[0253] Process Stage 1

[0254] A-1) Production of 2-Bromopyridine-5-carbaldehyde

[0255] 2-Bromopyridine-5-carbaldehyde is produced according to F. J.Romero-Salguerra et al. THL 40, 859 (1999).

[0256] A-2) Production of 2-Bromo-isonicotinic Acid

[0257] 160 g (0.93 mol) of 2-bromo-4-methyl-pyridine is added in dropsto 152 g (0.96 mol) of potassium permanganate in 4 l of water. Then, itis stirred under reflux for one hour before 152 g (0.96 mol) ofpotassium permanganate is added once again. After two additional hoursof stirring under reflux, it is suctioned off in a hot state over Celiteand washed with water. The aqueous phase is shaken out three times withdichloromethane. The aqueous phase is concentrated by evaporation toone-half of its original volume and set at pH 2 with concentratedhydrochloric acid. The precipitated solid is suctioned off and dried at70° C. in a vacuum. 56.5 g (28% of theory) of 2-bromo-isonicotinic acidaccumulates as a white solid product.

[0258] A-3) Production of 2-Bromo-4-hydroxymethyl-pyridine

[0259] 30.2 ml (295 mmol) of triethylamine is added to 56.5 g (280 mmol)of 2-bromo-isonicotinic acid in 1.2 l of tetrahydrofuran (THF). Then, itis cooled to −10° C. and mixed drop by drop with 38.2 ml (295 mmol) ofisobutyl formate. After one hour at −10° C., stirring was continued, itis cooled to −70° C. and mixed drop by drop with 590 ml (590 mmol) oflithium aluminum hydride (LiAlH₄) solution (1 M in THF). After stirringis continued for one hour at −70° C., it is allowed to reach −40° C. 600ml of 50% acetic acid is added. It is stirred overnight at roomtemperature. The insoluble components are suctioned off, and thefiltrate is concentrated by evaporation. The residue is purified onsilica gel with hexane and hexane/ethyl acetate 1:1. 28.0 g (55% oftheory) of 2-bromo-4-hydroxymethyl-pyridine accumulates as a whitesolidifying oil.

[0260] A4) Production of 2-Bromo-4-formyl-pyridine

[0261] 149 g (1714 mmol) of manganese dioxide is added in measuredquantities in 6 hours to 28.0 g (148.9 mmol) of2-bromo-4-hydroxymethyl-pyridine in 500 ml of dichloromethane. Then, itis stirred for 48 more hours at room temperature. It is suctioned off onCelite and concentrated by evaporation. 16.4 g (60% of theory) of2-bromo-4-formyl-pyridine accumulates as a solidifying white oil.

[0262] Process Stage 2

[0263] A-5) Production of2-[(6-Bromo-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide

[0264] 3.46 g (13.17 mmol) of 2-amino-N-isoquinolin-3-yl-benzamide isintroduced into 50 ml of methanol, mixed with 1.5 ml of glacial aceticacid as well as 2.45 g (13.17 mmol) of 2-bromopyridine-5-carbaldehydeand stirred for 24 hours under argon and in a moisture-free environmentat room temperature. Then, it is mixed with 828 mg (13.17 mmol) ofsodium cyanoborohydride and stirred for another 24 hours at roomtemperature. After concentration by evaporation under a vacuum, theresidue is taken up in dilute sodium bicarbonate solution and suctionedoff. The residue that is obtained is absorptively precipitated in alittle ethyl acetate and suctioned off again. The residue that isobtained in this case is on silica gel with hexane:ethyl acetate=1:1 asan eluant. 3.27 g (57% of theory) of2-[(6-bromo-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide isobtained.

[0265] A-6) Production ofN-(Isoquinolin-3-yl)-2-[3-bromopyridin-4-yl-methylamino]-benzoic AcidAmide

[0266] 263 mg (1 mmol) of N-(isoquinolin-3-yl)-2-aminobenzoic acid amideis mixed in 6 ml of MeOH in succession with 0.06 ml of glacial aceticacid, 298 mg (1.6 mmol) of 3-bromo-pyridine-4-carbaldehyde (producedaccording to Tetrahedron 2000, 347), and it is stirred for 24 hours atroom temperature. Then, 100 mg (1.6 mmol) of sodium cyanoborohydride isadded, and it is stirred for another 24 hours. It is then mixed with 50ml of dilute sodium bicarbonate solution, and the precipitated productis suctioned off. The residue is chromatographed on silica gel withmethylene chloride:ethanol=95:5 as an eluant.N-(Isoquinolin-3-yl)-2-[3-bromopyridin-4-yl-methylamino]-benzoic acidamide is obtained as a resin. The 3-bromo-pyridine-4-carbaldehyde thatis used is produced according to Chem. Pharm. Bull. 1970, 38, 2446.

[0267] Similarly produced is:

[0268] A-7)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide

[0269]¹H-NMR (CDCl₃): 9.00 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.35 (t,J=5.7, 1H), 8.30 (d, J=5.1, 1H), 7.92 (d, J=8.1, 1H), 7.86 (d, J=8.5,1H), 7.70-7.65 (m, 2H), 7.53-7.48 (m, 2H), 7.33-7.26 (m, 2H), 6.75 (t,J=7.8, 1H), 6.48 (d, J=8.5, 1H), 4.48 (d, J=5.9, 2H).

[0270] MS (CI, NH3): 435 (100%), 433 (100%)

[0271] A-8)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-2H-indol-6-yl)-Benzamide

[0272] A-9)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamide

[0273] A-10)2-[(6-Bromo-pyridin-3-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-Benzamide

[0274] A-11)2-[(6-Bromo-pyridin-3-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamide

[0275] A-12)2-[(6-Bromo-pyridin-3-ylmethyl)-amino]-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamide

[0276] A-13)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamide

[0277] A-14a)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-Benzamide

[0278] A-14b)2-[(6-Bromo-pyridin-3-ylmethyl)-amino]-N-(7-methoxy-3-methylquinolin-2-yl)-benzamide

[0279] Process Stage 3

[0280] A-15) Production of5-{[2-(Isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0281] 3.27 g (7.55 mmol) of2-[(6-bromo-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-benzamide ismixed in 75 ml of dimethylformamide with 2.2 ml of triethylamine, 36 mlof water, 362 mg (0.65 mmol) of bisdiphenylphosphinoferrocene and 75 mg(0.33 mmol) of palladium(II) acetate, and it is shaken in an autoclaveunder carbon monoxide at a pressure of 3 bar and a temperature of 50° C.for 3 hours. After cooling, it is suctioned off on diatomaceous earthand concentrated by evaporation. The residue is taken up in water, setat pH 5-6 with glacial acetic acid, suctioned off, and the filter cakesare rewashed with hexane. 3.35 g of5-{[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicacid, which is further reacted without further purification, isobtained.

[0282] Similarly produced are:

[0283] A-16)4-{[2-(Isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0284] A-17)4-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0285] A-18)5-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0286] A-19)4-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0287] A-20)5-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0288] A-21)5-{[2-(7-Methoxy-2-oxo-2H-chromen-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0289] A-22)4-{[2-(7-Methoxy-2-oxo-2H-chromen-3-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0290] A-23)4-{[2-(7-Methoxy-3-methyl-quinolin-2-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0291] A-24)5-{[2-(7-Methoxy-3-methyl-quinolin-2-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0292] A-25)5-{[2-(1-Methyl-1H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0293] A-26)4-{[2-(1-Methyl-1H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0294] A-27)4-{[2-(2-Methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0295] A-28)5-{[2-(2-Methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0296] A-29)4-{[2-(3-Trifluoromethyl-phenylcarbamoyl)-phenylamino]-methyl}-pyridine-2-carboxylicAcid

[0297] Melting point 151° C.

[0298] A-30)4-{[2-(1H-Indazol-6-ylcarbamoyl)-phenylamino]methyl}-pyridine-2-carboxylicAcid

[0299] A-31)4-{[2-(1H-Indazol-5-ylcarbamoyl)-phenylamino]methyl}-pyridine-2-carboxylicAcid

EXAMPLE B

[0300] Process Stage 1

[0301] B-1) Production of 5-Nitro-1,3-dihydro-indol-2-one

[0302] 5-Nitro-1,3-dihydro-indol-2-one is produced according to R. T.Courts, J. Org. Chem. 48, 3747, (1970).

[0303] B-2) Production of Dinitrophenylacetic Acid Methyl Ester.

[0304] 22.6 g (100 mmol) of 2,4-dinitrophenylacetic acid is dissolved ina mixture of 200 ml of methanol and 830 ml of toluene and mixed at roomtemperature with 83 ml of trimethylsilyldiazomethane (2 mol in toluene;166 mmol), and it is stirred for 3 hours at room temperature. Afterevaporation to the dry state and drying at 70° C. in a vacuum, 24 g(100% of theory) of 2,4-dinitrophenylacetic acid methyl ester isobtained.

[0305] B-3) Production of 6-Nitro-1,3-dihydro-indol-2-one

[0306] 20 g (83 mmol) of 2,4-dinitrophenylacetic acid methyl ester ishydrogenated in 400 ml of glacial acetic acid with 2.1 g ofpalladium/carbon (10%) under 20 bar of hydrogen for 1.5 hours at roomtemperature. After catalyst is filtered out, it is concentrated byevaporation and very quickly dried on solid potassium hydroxide in avacuum. The residue is chromatographed on silica gel with a gradientthat consists of methylene chloride:ethanol=97.5:2.5 to 90:10 as aneluant. After recrystallization from ethyl acetate, 4 g (30% of theory)of 6-nitro-1,3-dihydro-indol-2-one with a melting point of 206° C. isobtained.

[0307] Process Stage 2

[0308] B4) Production of 5-Amino-1,3-dihydro-indol-2-one

[0309] 356 mg of 5-nitro-1,3-dihydro-indol-2-one is hydrogenated in 30ml of tetrahydrofuran:ethanol=1:1 with 400 mg of palladium on carbon(10%) at room temperature and normal pressure for 1 hour. After thecatalyst is suctioned off on diatomaceous earth and after concentrationby evaporation, 320 mg (100% of theory) of5-amino-1,3-dihydro-indol-2-one is obtained.

[0310] B-5) Production of 6-Amino-1,3-dihydro-indol-2-one

[0311] Similarly produced from the corresponding nitro compound is6-amino-1,3-dihydro-indol-2-one.

[0312] Process Stage 3

[0313] B-6) 2-Nitro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamide

[0314] 320 mg of 5-amino-1,3-dihydro-indol-2-one is dissolved in 1 ml ofdimethylacetamide and mixed drop by drop with 371 mg (2 mmol) of2-nitrobenzoyl chloride, whereby a slight heating occurs. After stirringovernight at room temperature, it is concentrated by evaporation in avacuum, and the residue is taken up in ethyl acetate and water. Thesuctioning-off of an insoluble solid provides 130 mg (21.9% of theory)of 2-nitro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamide. After shakingout, the organic phase is washed, filtered and concentrated byevaporation, and 400 mg (67% of theory) of2-nitro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamide with a meltingpoint of 265° C. is obtained again.

[0315] B-7) Production of2-Nitro-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide

[0316] Produced similarly to I) is2-nitro-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide with a meltingpoint >300° C.

[0317] Process Stage 4

[0318] B-8) Production of 2-Amino-N-(indol-2-on-5-yl)benzoic Acid Amide

[0319] Produced in a way similar to process stage 2 is also2-amino-N-(indol-2-on-5-yl)benzoic acid amide with a melting point of219° C.

[0320] B-9) Production of 2-Amino-N-(indol-2-on-6-yl)benzoic Acid Amide

[0321] Produced in a way similar to stage 2 is also2-amino-N-(indol-2-on-6-yl)benzoic acid amide with a melting point of230° C.

EXAMPLE C

[0322] C-1) Production of2-Amino-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamide

[0323] Process Stage 1

[0324] C-2) Production of 3-Nitro-7-methoxy-chromen-2-one

[0325] 13 g (85.4 mmol) of 2-hydroxy-4-methoxybenzaldehyde is heated in300 ml of toluene with 9.8 g (102.5 mmol) of n-propylamine hydrochlorideand 11.5 ml (102.5 mmol) of nitroacetic acid ethyl ester for 15 hours ina water separator. 3 ml of nitroacetic acid ethyl ester is then addedagain and boiled for another 5 hours in a water separator. Aftercooling, it is diluted with ethyl acetate and shaken out with water. Theethyl acetate phase is dried, filtered and concentrated by evaporation.The residue is chromatographed on silica gel with methylene chloride asan eluant. 6.14 g (33% of theory) of 3-nitro-7-methoxy-chromen-2-one isobtained.

[0326] Process Stage 2

[0327] C-3) Production of 3-Amino-7-methoxy-chromen-2-one

[0328] In a way similar to process stage 2 of Example B,3-amino-7-methoxy-chromen-2-one is produced from3-nitro-7-methoxy-chromen-2-one in ethanol.

[0329] Process Stage 3

[0330] C4) Production of2-Nitro-N-(7-methoxybenzopyran-2-on-3-yl)benzoic Acid Amide

[0331] In a way similar to process stage 3 from Example B,2-nitro-N-(7-methoxybenzopyran-2-on-3-yl)benzoic acid amide is producedfrom 2-nitrobenzoyl chloride and 3-amino-7-methoxy-chromen-2-one and2-nitro-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamide.

[0332] Process Stage 4

[0333] C-5) Production of2-Amino-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-Benzamide

[0334] In a way similar to process stage 2 from Example B, the2-amino-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamide is produced from2-nitro-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamine inethanol:tetrahydrofuran=5:2.

EXAMPLE D

[0335] D-1) Production of2-[(6-Cyano-pyridin-3-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamide

[0336] 219 mg (0.5 mmol) of2-[(6-bromo-pyridin-3-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamideis added into 7 ml of dimethyl acetamide with 59 mg (0.5 mmol) ofzinc(II)cyanide, 12 mg (0.013 mmol) of tris(dibenzylideneacetone)-dipalladium, 10 mg (0.018 mmol) ofbis(diphenylphosphino)ferrocene and 4 mg (0.06 mmol) of zinc powder, andit is stirred under argon and in a moisture-free environment for 7.5hours at a bath temperature of 150° C. After cooling, it is diluted withwater, shaken out with ethyl acetate, and the organic phase is dried,filtered and concentrated by evaporation. The residue is chromatographedon silica gel with a gradient of methylene chloride:ethanol=97.5:2.5 to90:10 as an eluant. 65 mg (30% of theory)of2-[(6-cyano-pyridin-3-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamideis obtained.

[0337] Similarly produced are:

[0338] D-2)2-[(6-Cyano-pyridin-3-ylmethyl)-amino]-N-(7-methoxy-2-oxo-2H-chromen-3-yl)-benzamide

EXAMPLE E

[0339] Process Stage 1

[0340] E-1) Production of 2-Chloro-nicotinic Acid Methyl Ester

[0341] 5.6 g of 2-chloro-nicotinic acid is dissolved in 280 ml oftoluene and 80 ml of methanol and mixed with 37.4 ml (74.8 mmol) oftrimethylsilyldiazomethane (2 mol in hexane) and stirred for 3 hours atroom temperature. After the batch is concentrated by evaporation, 7 g(100% of theory) of 2-chloro-nicotinic acid methyl ester is obtained.

[0342] Process Stage 2

[0343] E-2) Production of 2-[(Pyridin-4-ylmethyl)-amino]-nicotinic AcidMethyl Ester

[0344] 4.0 g (23.3 mmol) of 2-chloro-nicotinic acid methyl ester isheated with 2.52 g (23.3 mmol) of 4-aminomethylpyridine for 1.5 hours toa bath temperature of 100° C. After cooling, it is diluted with 100 mlof dilute sodium bicarbonate solution and shaken out three times with 50ml of ethyl acetate each. The combined organic phase is washed, dried,filtered and concentrated by evaporation. The residue is chromatographedon silica gel with methylene chloride:ethanol=10:1 as an eluant. 1.36 g(24% of theory) of 2-[(pyridin-4-ylmethyl)-amino]-nicotinic acid methylester is obtained.

[0345] Similarly produced is:

[0346] E-3) 2-[(Pyridin-3-ylmethyl)-amino]-nicotinic Acid Methyl Ester

[0347] Process Stage 3

[0348] E4) Production of 2-[(1-Oxy-pyridin-4-ylmethyl)-amino]-nicotinicAcid Methyl Ester

[0349] 2.09 g (8.59 mmol) of 2-[(pyridin-4-ylmethyl)-amino]-nicotinicacid methyl ester is mixed in 150 ml of methylene chloride with 2.21 g(9.88 mmol) of m-chloroperbenzoic acid, and it is stirred for 24 hoursat room temperature. It is mixed with 50 ml of dilute sodium bicarbonatesolution, shaken, the organic phase is separated and extracted threetimes with 50 ml of methylene chloride each. The combined organic phaseis washed, dried, filtered and concentrated by evaporation. 2.7 g (100%of theory) of 2-[(1-oxy-pyridin-4-ylmethyl)-amino]-nicotinic acid methylester is obtained as an oil.

[0350] Similarly produced is:

[0351] E-5) 2-[(1-Oxy-pyridin-3-ylmethyl)-amino]-nicotinic Acid MethylEster

[0352] Process Stage 4

[0353] E-6) Production of2-[(2-Cyano-pyridin-4-ylmethyl)-amino]-nicotinic Acid Methyl Ester

[0354] 2.7 g (10.4 mmol) of2-[(1-oxy-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester isheated in 52 ml of dimethylformamide in a pressure vessel together with3.15 g (31.2 mmol) of triethylamine and 9.19 g (62.4 mmol) oftrimethylsilyl cyanide for 8 hours to a bath temperature of 110° C.After concentration by evaporation in a vacuum, the residue is taken upin 100 ml of dilute sodium bicarbonate solution and extracted threetimes with 100 ml of ethyl acetate each. The combined organic phase iswashed, dried, filtered and concentrated by evaporation. The residue ischromatographed on a flash column (50 g; Isolute flash silica; SepartisCompany) with a gradient of methylene chloride:ethanol=100:0 to 95:5 asan eluant. 1.31 g (47% of theory) of2-[(2-cyano-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester isobtained.

[0355] Similarly produced is:

[0356] E-7) Production of2-[(6-Cyano-pyridin-3-ylmethyl)-amino]-nicotinic Acid Methyl Ester

[0357] In the production, a small amount of2-[(2-cyano-pyridin-3-ylmethyl)-amino]-nicotinic acid methyl esteraccumulates at the same time.

[0358] Process Stage 5

[0359] E-8) Production of2-[(2-Cyano-pyridin-4-ylmethyl)-amino]-N-isoquinolin-3-yl-nicotinamide

[0360] In 10 ml of toluene, 277 mg (1.92 mmol) of 3-aminoisoquinolineand 0.86 ml of trimethylaluminum (2 mol solution in toluene) are stirredunder argon and in a moisture-free environment for 30 minutes at 4° C.468 mg (1.74 mmol) of 2-[(2-cyano-pyridin-4-ylmethyl)-amino]-nicotinicacid methyl ester is then added and refluxed for 2 hours. It is mixedwith 30 ml of dilute sodium bicarbonate solution and shaken out threetimes with 30 ml of ethyl acetate each. The combined organic phase iswashed, dried, filtered and concentrated by evaporation. The residue ischromatographed on a flash column (20 g; Isolute flash silica; SepartisCompany) with a gradient of methylene chloride:ethanol=100:0 to 95:5 asan eluant. 400 mg (60% of theory) of2-[(2-cyano-pyridin-4-ylmethyl)-amino]-N-isoquinolin-3-yl-nicotinamideis obtained.

[0361] E-9)N-(Isoquinolin-3-yl)-2-[2-cyanopyridin-4-yl-methylamino]-benzoic AcidAmide

[0362] 920 mg (2.5 mmol) ofN-(isoquinolin-3-yl)-2-(4-pyridylmethyl)-aminobenzoic acid amide-N-oxideis mixed in a glass pressure vessel in succession with 20 ml ofdimethylformamide in succession with 760 mg (7.5 mmol) of triethylamineand 1.24 g (12.5 mmol) of trimethylsilylcyanide and then heated for 10hours to a bath temperature of 110° C. It is then diluted with water toabout 200 ml and shaken out three times with 50 ml of ethyl acetateeach. The collected organic phase is washed with 50 ml of water, dried,filtered and concentrated by evaporation. The residue is chromatographedfirst on silica gel with ethyl acetate:hexane=1:1 and then again onsilica gel with dichloromethane:ethanol=100:2 as an eluant. 132 mg (14%of theory) ofN-(isoquinolin-3-yl)-2-(4-2-cyanopyridylmethyl)amino-benzoic acid amideis obtained as a resin.

[0363] If the production of the intermediate compounds is not described,the latter are known or can be produced analogously to the knowncompounds or the processes that are described here.

[0364] Similarly produced are:

[0365] E-10)2-[(2-Cyano-pyridin-3-ylmethyl)-amino]-N-isoquinolin-3-yl-nicotinamide

[0366] E-11)2-[(6-Cyano-pyridin-3-ylmethyl)-amino]-N-isoquinotin-3-yl-nicotinamide

EXAMPLE F

[0367] 1. Process Stage

[0368] F-1) Production of 2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-benzoicAcid-Methyl Ester

[0369] 6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml ofmethanol is mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) of2-bromopyridine-4-carbaldehyde and stirred overnight at 40° C. 3.8 g (60mmol) of sodium cyanoborohydride is added thereto, and it is stirredovernight at 40° C. 3.8 g (60 mmol) of sodium cyanoborohydride is addedagain and stirred over the weekend at 40° C. It is mixed with water andlargely concentrated by evaporation. The aqueous phase is extracted withethyl acetate, and the combined organic phases are dried, filtered andconcentrated by evaporation. The crude product is chromatographed onsilica gel with a gradient that consists of hexane and hexane/ethylacetate 1:3 and hexane/ethyl acetate 1:1 as an eluant. 10.0 g (78% oftheory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methylester is obtained as a colorless oil.

[0370] 2. Process Stage

[0371] F-2) Production of 2-[(2-Cyano-pyridin-4-ylmethyl)-amino]-benzoicAcid Methyl Ester

[0372] 1.28 g (4.0 mmol) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester in 140ml of dimethylacetamide is mixed with 0.532 g (4.56 mmol) of zinc(II)cyanide, 0.072 g (0.08 mmol) of tris-(dibenzylideneacetone)-dipalladium,0.088 g (0.16 mmol) of bis-(diphenylphosphino)-ferrocene and 0.029 g(0.46 mmol) of zinc powder. It is stirred for 6 hours at 150° C. Aftercooling, the reaction mixture is poured into water. It is extractedthree times with ethyl acetate; the combined organic phases are dried onsodium sulfate and concentrated by evaporation. The reaction product ischromatographed on silica gel with a gradient that consists ofhexane:ethyl acetate 100:0 to 50:50 as an eluant. 0.887 g (83% oftheory) of 2-[(2-cyano-pyridin-4-ylmethyl)-amino]-benzoic acid methylester is obtained in the form of a yellow solid.

[0373] 3. Process Stage

[0374] F-3)2-[(2-Cyano-pyridin-4-ylmethyl)amino]-N-(7-methoxy-3-methyl-quinolin-2-yl)-benzamide

[0375] At 0° C., 0.25 ml of trimethylaluminum (2 M in toluene) is addedin drops to 0.094 g (0.5 mmol) of 7-methoxy-3-methyl-quinolin-2-ylaminein 4 ml of toluene. After 10 minutes of continuous stirring at 0° C.,0.133 g (0.5 mmol) of 2-[(2-cyano-pyridin-4-ylmethyl)-amino]-benzoicacid methyl ester in 2 ml of toluene is added in drops. Then, it isrefluxed for 2 hours and stirred overnight at room temperature. Theprecipitate is suctioned off and suspended in saturated sodiumbicarbonate solution. Then, ethylenediaminetetraacetic acid is added. Itis shaken out with ethyl acetate, dried on sodium sulfate andconcentrated by evaporation. Column-chromatographic purification onsilica gel with a gradient of hexane:acetone=100:0 to 50:50 as an eluantyields 0.113 g (54% of theory) of2-[(2-cyano-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-3-methyl-quinolin-2-yl)-benzamideas a yellow foam.

EXAMPLE G

[0376] 1. Process Stage G1) Production of2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-benzoic Acid

[0377] 10.0 g (31.2 mmol) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester isdissolved in 290 ml of ethanol and mixed with 31.2 ml of 2 M sodiumhydroxide solution. After it has been stirred overnight at roomtemperature, the ethanol is drawn off, and the aqueous phase is shakenout with ethyl acetate. The aqueous phase is acidified with concentratedhydrochloric acid. The precipitate that is formed is suctioned off anddried. 5.93 g (62%) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoicacid accumulates in the form of a white solid.

[0378] 2. Process Stage

[0379] G2) Production of2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide

[0380] 0.500 g (1.6 mmol) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid, 0.471 g (3.2 mmol)of 2-methyl-2H-indazol-6-ylamine, 0.4 ml (3.68 mmol) ofN-methylmorpholine and 0.729 g (1.92 mmol) ofO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(HATU) in 25 ml of dimethylformamide are stirred for 16 hours at roomtemperature. The dimethylformamide is drawn off in an oil pump vacuum.The remaining residue is taken up in saturated sodium bicarbonatesolution. It is extracted three times with ethyl acetate, and thecombined organic phases are dried, filtered and concentrated byevaporation. The residue is chromatographed on silica gel with agradient that consists of hexane:acetone=100:0 to 50:50 as an eluant.0.669 g (96% of theory) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamideis obtained in the form of a beige foam.

[0381] Similarly produced are:

[0382] G3)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1-methyl-1H-indazol-6-yl)-benzamide

[0383] G4)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1H-indazol-6-yl)-benzamide

[0384] G-5)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(1H-indazol-5-yl)-benzamide

[0385] G6)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide

[0386] G-7)2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzamide

[0387] H-1) 4-(tert-Butoxycarbonylamino-methyl)-pyridine-2-carboxylicAcid

[0388] 4-(tert-Butoxycarbonylamino-methyl)-pyridine-2-carboxylic acid isproduced according to Chem. Eur. J. 2, 2000, 216 from(2-cyano-pyridin-4-ylmethyl)-carbamic acid-tert-butyl ester.

[0389] H-2) Optically Active[2-(2-Hydroxy-propylcarbamoyl)-pyridin-4-ylmethyl]-carbamicAcid-tert-butyl Ester

[0390] Optically active[2-(2-hydroxy-propylcarbamoyl)-pyridin-4-ylmethyl]-carbamicacid-tert-butyl ester is produced according to the process, provided inExample 2.0, from4-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylic acid andS-(+)-1-amino-2-propanol in a yield of 91%.

[0391] H-3) Optically Active 4-Aminomethyl-pyridine-2-carboxylic Acid(2-Hydroxy-propyl)-amide

[0392] 480 mg (1.7 mmol) of[2-(2-hydroxy-propylcarbamoyl)-pyridin-4-ylmethyl]-carbamicacid-tert-butyl ester is mixed in 30 ml of ethanol with 17 ml of 1Nhydrochloric acid and heated to a bath temperature of 110° C. for threehours while nitrogen is passing through it. The batch is concentrated byevaporation in a vacuum and dried and used in Example 5.0 withoutfurther purification.

[0393] H-4) 2-Chloro-N-isoquinolin-3-yl-nicotinamide

[0394] 2.9 g (20 mmol) of 3-aminoisoquinoline is suspended in 45 ml oftetrahydrofuran and mixed drop by drop with a solution of 3.5 g (20mmol) of 2-chloro-nicotinoyl chloride in 45 ml of tetrahydrofuran. Afterstirring overnight at room temperature, the batch is suctioned off, andthe residue is rewashed with tetrahydrofuran. The residue is suspendedand suctioned off again as well as dried. 3.14 g (55% of theory) of2-chloro-N-isoquinolin-3-yl-nicotinamide is obtained.

[0395] The sample applications below explain the biological action andthe use of the compounds according to the invention without the latterbeing limited to the examples.

[0396] Solutions Required for the Tests

[0397] Stock solutions

[0398] Stock solution A: 3 mmol of ATP in water, pH 7.0 (−70° C.)

[0399] Stock solution B: g-33 P-ATP 1 mCi/100 μl

[0400] Stock solution C: poly-(Glu4 Tyr) 10 mg/ml in water

[0401] Solution for dilutions

[0402] Substrate solvent: 10 mmol of DTT, 10 mmol of manganese chloride,100 mmol of magnesium chloride

[0403] Enzyme solution: 120 mmol of tris/HCl, pH 7.5, 10 μM of sodiumvanadium oxide

[0404] Sample Application 1

[0405] Inhibition of the KDR- and FLT-1 Kinase Activity in the Presenceof the Compounds According to the Invention

[0406] In a microtiter plate (without protein binding) that tapers to apoint, 10 μl of substrate mix (10 μl of volume of ATP stock solutionA+25 μCi of g-33P-ATP (about 2.5 μl of stock solution B)+30 μl ofpoly-(Glu4Tyr) stock solution C+1.21 ml of substrate solvent), 10 μl ofinhibitor solution (substances corresponding to the dilutions, 3% DMSOin substrate solvent as a control) and 10 μl of enzyme solution (11.25μg of enzyme stock solution (KDR or FLT-1 kinase) are added at 4° C. in1.25 ml of enzyme solution (dilute). It is thoroughly mixed andincubated for 10 minutes at room temperature. Then, 10 μl of stopsolution (250 mmol of EDTA, pH 7.0) is added, mixed, and 10 μl of thesolution is transferred to a P 81 phosphocellulose filter. Then, it iswashed several times in 0.1 M phosphoric acid. The filter paper isdried, coated with Meltilex and measured in a microbeta counter.

[0407] The IC50 values are determined from the inhibitor concentration,which is necessary to inhibit the phosphate incorporation to 50% of theuninhibited incorporation after removal of the blank reading(EDTA-stopped reaction).

[0408] The results of the kinase inhibition IC50 in nM are presented inthe table below: VEGFR II (KDR) Example No. [nM] 1.32 40

[0409] Sample Application 2

[0410] Cytochrome P450 Inhibition

[0411] The Cytochrome P450 inhibition was performed according to thepublication of Crespi et al. (Anal. Biochem., 248, 188-190 (1997)) withuse of baculovirus/insect cell-expressed, human Cytochrome P 450isoenzymes (1A2, 2C9, 2C19, 3A4).

[0412] The results are presented in the following table. Inhibition ofthe Cytochrome P450 Isoenzymes (IC50, μM) Cytochrome 1A2 2C9 2C19 3A4P450 Isoenzyme Example 5.2 0.2 0.05 3.6 2.54 of WO 00/27819 Example 302.9 4.9 25 1.32

[0413] The superior action of the compounds according to the inventioncompared to the known compounds can be seen clearly from the result,i.e., the compounds according to the invention show a significantlyslighter inhibition of the detoxifying P450 system than the knowncompounds, which results in significantly fewer interactions with otheractive ingredients.

1. Compounds of general formula I

in which A, B and D, independently of one another, stand for a nitrogen or carbon atom, whereby at least one nitrogen atom is contained in the ring, E stands for aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl or with the group —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹, G stands for a nitrogen atom or for the group —C—X, L stands for a nitrogen atom or for the group —C—X, M stands for a nitrogen atom or for the group —C—X, Q stands for a nitrogen atom or for the group —C—X, whereby at most one nitrogen atom is in the ring, X stands for hydrogen, halogen or for C₁-C₆-alkyl, C₁-C₆-alkyloxy or C₁-C₆-carboxyalkyl that is unsubstituted or optionally substituted in one or more places with halogen, R¹ stands for branched or unbranched C₁-C₁₂-alkyl or C₂-C₁₂-alkenyl that is optionally substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyloxy, aralkyloxy, C₁-C₆-alkyl and/or with the group —NR²R³; or for C₃-C₁₀-cycloalkyl or C₃-C₁₀-cycloalkenyl that is optionally substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyloxy, C₁-C₆-alkyl and/or with the group —NR²R³; or for aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, hydroxy, C₁-C₆-alkyloxy, C₂-C₆-alkenyl, aryl-C₁-C₆-alkyloxy, aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group ═O, —SO₂R⁴, OR⁵, —R⁵ or —PO(OR¹²)(OR¹³), R² and R³, independently of one another, stand for hydrogen or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, phenyl, hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, or with the group —NR⁶R⁷, —OR⁵, C—C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or R² and R³, together with the nitrogen atom, form a C₃-C₈-ring, which optionally can contain another nitrogen, sulfur or oxygen atom in the ring, or can contain the group —N(R¹⁰), and which optionally can be substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group —OR 5-SR⁴, —SOR⁴ or —SO₂R⁴, R⁴ stands for hydroxy, C₁-C₆-alkyl, aryl, heteroaryl or for the group —NR²R³, R⁵ stands for hydrogen, C₁-C₁₂-alkyl, halo-C₁-C₆-alkyl, C₃-C₆-cycloalkyl or halo-C₃-C₆-cycloalkyl, or for C₁-C₁₂-alkyl, which is interrupted in one or more places with oxygen or stands for the group —(CH₂)₂NR²R³, —CH₂CN or —CH₂CF₃, R⁶ and R⁷, independently of one another, stand for hydrogen or C₁-C₆-alkyl, or R⁶ and R⁷ together form a 5- to 7-membered ring that can contain an oxygen or sulfur atom or the group —N(R¹⁰)—, R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl, aryl or hetaryl that is optionally substituted with halogen in one or more places, R⁹ stands for hydrogen, C₁-C₆-alkyl, tri-C₁₋₆-alkylsilyl, aryl, hetaryl, or for the group —COR¹¹, R¹⁰ stands for hydrogen, C₁-C₆-alkyl or aryl, R¹¹ stands for hydrogen, C₁-C₆-alkyl or for the group —NR²R³, and R¹² and R³, independently of one another, stand for hydrogen or C—C₆-alkyl, as well as isomers, enantiomers and salts thereof.
 2. Compounds of general formula I, according to claim 1, in which A, B, and D, independently of one another, stand for a nitrogen or carbon atom, whereby at least one nitrogen atom is contained in the ring, E stands for aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl or with the group —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹, G stands for a nitrogen atom or for the group —C—X, L stands for a nitrogen atom or for the group —C—X, M stands for a nitrogen atom or for the group —C—X, Q stands for a nitrogen atom or for the group —C—X,  whereby at most one nitrogen atom is in the ring, X stands for hydrogen, halogen or for C₁-C₆-alkyl, C₁-C₆-alkyloxy or C₁-C₆-carboxyalkyl that is unsubstituted or that is optionally substituted in one or more places with halogen, R¹ stands for aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, hydroxy, C₁-C₆-alkyloxy, C₂-C₆-alkenyl, aryl-C₁-C₆-alkyloxy, aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group ═O, —SO₂R⁴, OR⁵, —R⁵ or —PO(OR¹²)(OR¹³), R² and R³, independently of one another, stand for hydrogen or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, phenyl, hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —NR⁶R⁷, —OR⁵, C₁-C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or R² and R³ together with the nitrogen atom form a C₃-C₈ ring, which optionally can contain another nitrogen, sulfur or oxygen atom in the ring, or can contain the group —N(R¹⁰), and which optionally can be substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group —OR⁵, —SR⁴, —SOR⁴ or  —SO₂R⁴, R⁴ stands for hydroxy, C₁-C₆-alkyl, aryl, heteroaryl or for the group —NR²R³, R⁵ stands for hydrogen, C₁-C₁₂-alkyl, halo-C₁-C₆-alkyl, C₃-C₆-cycloalkyl or halo-C₃-C₆-cycloalkyl, or for C₁-C₁₂-alkyl, which is interrupted in one or more places with oxygen, or stands for the group —CH₂)₂NR²R³, —CH₂CN or —CH₂CF₃, R⁶ and R⁷, independently of one another, stand for hydrogen or C₁-C₆-alkyl, or R⁶ and R⁷ together form a 5- to 7-membered ring, which can contain an oxygen or sulfur atom or the group —N(R¹⁰)—, R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl, aryl or hetaryl that is optionally substituted with halogen in one or more places, R⁹ stands for hydrogen, C₁-C₆-alkyl, tri-C₁-C₆-alkylsilyl, aryl, hetaryl or for the group —COR¹¹, R¹⁰ stands for hydrogen, C₁-C₆-alkyl or aryl, R¹¹ stands for hydrogen, C₁-C₆-alkyl or for the group —NR²R³, and R¹² and R³, independently of one another, stand for hydrogen or C—C₆-alkyl, as well as isomers, enantiomers and salts thereof.
 3. Compounds of general formula I, according to claim 1 and 2, in which A, B and D, independently of one another, stand for a nitrogen or carbon atom, whereby at least one nitrogen atom is contained in the ring, E stands for aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, halo-C₁-C₆alkyl or with the group —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹, G stands for a nitrogen atom or for the group —C—X, L stands for a nitrogen atom or for the group —C—X, M stands for a nitrogen atom or for the group —C—X, Q stands for a nitrogen atom or for the group —C—X, whereby at most one nitrogen atom is in the ring, X stands for hydrogen or halogen, R¹ stands for aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyloxy, aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —SO₂R⁴, OR⁵, —R⁵ or —PO(OR¹²)(OR¹³), R² and R³, independently of one another, stand for hydrogen or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, phenyl, hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —NR⁶R⁷—OR⁵, C₁-C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or R² and R³ together with the nitrogen atom form a C₃-C₈-ring, which optionally can contain another nitrogen, sulfur or oxygen atom in the ring, or can contain the group —N(R¹⁰), and which optionally can be substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, R⁴ stands for hydroxy or for the group —NR²R³, R⁵ stands for hydrogen, C₁-C₁₂-alkyl or for C₁-C₁₂-alkyl, which is interrupted in one or more places with oxygen or stands for the group —(CH₂)₂NR²R³, —CH₂CN or —CH₂CF₃, R⁶ and R⁷, independently of one another, stand for hydrogen or C₁-C₆-alkyl, or R⁶ and R⁷ together form a 5- to 7-membered ring, which can contain an oxygen or sulfur atom or the group —N(R¹⁰)—, R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl, aryl or hetaryl that is optionally substituted with halogen in one or more places, R⁹ stands for hydrogen, C₁-C₆-alkyl, tri-C₁-C₆-alkylsilyl, aryl, hetaryl or for the group —COR¹¹, R¹⁰ stands for hydrogen, C₁-C₆-alkyl or aryl, R¹¹ stands for hydrogen, C₁-C₆-alkyl or for the group —NR²R³, and R¹² and R³, independently of one another, stand for hydrogen or C₁-C₆-alkyl, as well as isomers, enantiomers and salts thereof.
 4. Compounds of general formula I, according to claims 1 to 3 claim 1, in which A, B and D stand for a nitrogen or carbon atom, whereby at least one nitrogen atom is contained in the ring, E stands for hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁₋₆alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl or with the group —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or for the group —COOR⁸, —CONR²R³, —SR⁴, —SOR⁴, —SO₂R⁴, —SCN, —PO(OR¹²)(OR¹³), —CH═CH—COR⁹ or —C≡C—R⁹, G stands for the group —C—X, L stands for the group —C—X, M stands for the group —C—X, Q stands for a nitrogen atom or for the group —C—X, X stands for hydrogen or halogen, R¹ stands for phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline, or isoquinoline that is optionally substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyloxy, aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —SO₂R⁴, OR⁵, —R⁵ or —PO(OR¹²)(OR¹³) or is substituted on the group

 in which T stands for hydrogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, R² and R³, independently of one another, stand for hydrogen or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, aryl or hetaryl that is optionally substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, phenyl, hydroxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —NR⁶R⁷, —OR⁵, C₁-C₆-alkyl-OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, or R² and R³, together with the nitrogen atom, form a C₃-C₈-ring, which optionally can contain another nitrogen, sulfur or oxygen atom in the ring, or can contain the group —N(R¹⁰), and which optionally can be substituted in one or more places in the same way or differently with halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, aryl or with the group —OR⁵, —SR⁴, —SOR⁴ or —SO₂R⁴, R⁴ stands for hydroxy or for the group —NR²R³, R⁵ stands for hydrogen, C₁-C₁₂-alkyl or for C₁-C₁₂-alkyl, which is interrupted in one or more places with oxygen, or stands for the group —CH₂)₂NR²R³, —CH₂CN, or —CH₂CF₃, R⁶ and R⁷, independently of one another, stand for hydrogen or C₁-C₆-alkyl, or R⁶ and R⁷ together form a 5- to 7-membered ring that can contain an oxygen or sulfur atom, R⁸ stands for hydrogen or for C₁-C₆-alkyl, C₁-C₆-alkoxy, benzyl, aryl or hetaryl that is optionally substituted in one or more places with halogen, and R⁹ stands for hydrogen, C₁-C₆-alkyl or tri-C₁-C₆-alkylsilyl, and R¹² and R³, independently of one another, stand for hydrogen or C₁-C₆-alkyl, as well as isomers, enantiomers and salts thereof.
 5. Compounds of general formula I, according to claim 1, in which A, B and D, independently of one another, stand for a nitrogen or carbon atom, whereby at least one nitrogen atom is contained in the ring, E stands for thienyl, pyridyl or for the group —COOR⁸, —CONR²R³, or —C≡C—R⁹, G stands for the group —C—X, L stands for the group —C—X, M stands for the group —C—X, Q stands for a nitrogen atom or for the group —C—X, X stands for hydrogen or halogen, R¹ stands for phenyl, thiophene, furan, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, triazine, quinoline or isoquinoline that is optionally substituted in one or more places in the same way or differently with halogen, hydroxy, C₁-C₆-alkyloxy, aralkyloxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl or with the group —SO₂R⁴, OR⁵, —R⁵ or —PO(OR¹²)(OR¹³) or substituted on the group

 in which T stands for hydrogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, R² and R³, independently of one another, stand for hydrogen or for C₁-C₆-alkyl, C₃-C₆-cycloalkyl, phenyl or pyridyl that is optionally substituted in one or more places in the same way or differently with halogen, C₁-C₆-alkyl, phenyl or with the group —NR⁶R⁷, —OR⁵ or C₁-C₆-alkyl-OR⁵, or R² and R³ together with the nitrogen atom form a C₃-C₈-ring, which optionally can contain another nitrogen or oxygen atom in the ring, and which optionally can be substituted in one or more places in the same way or differently with C₁-C₆-alkyl, R⁴ stands for hydroxy or for the group —NR²R³, R⁵, R⁶ and R⁷, independently of one another, stand for hydrogen or C₁-C₆-alkyl, or R⁶ and R⁷ together form a 5- to 7-membered ring, which can contain an oxygen or sulfur atom, R⁸ stands for hydrogen, C₁-C₆-alkyl or benzyl, and R⁹ stands for hydrogen, C₁-C₆-alkyl or tri-C₁-C₆-alkylsilyl, and R¹² and R³, independently of one another, stand for hydrogen or C₁-C₆-alkyl, as well as isomers and salts thereof.
 6. Pharmaceutical agents that contain at least one compound according to claim
 1. 7. Pharmaceutical agents according to claim 6 for use in the case of psoriasis, Kaposi's sarcoma, restenosis, such as, e.g., stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such as diabetic retinopathy, neovascular glaucoma; renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver, mesangial cell proliferative diseases, arteriosclerosis, injuries to nerve tissue, inhibition of the reocclusion of vessels after balloon catheter treatment, vascular prosthetics or use of mechanical devices to keep vessels open, such as, e.g., stents, and as immunosuppressive agents, and for supporting scar-free healing, in senile keratosis and in contact dermatitis.
 8. Pharmaceutical agents according to claim 6 for use as VEGFR kinase 3-inhibitors in lymphangiogenesis and in hyper- and dysplastic changes of the lymphatic system.
 9. Compounds according to claim 1, with suitable formulation substances and vehicles.
 10. Use of the compounds of formula I, according to claim 1, as inhibitors of the tyrosine kinases KDR and FLT.
 11. Use of the compounds of general formula I, according to claim 1 in the form of a pharmaceutical preparation for enteral, parenteral and oral administration.
 12. Use of the compounds according to claim 1 in the case of psoriasis, Kaposi's sarcoma, restenosis, such as, e.g., stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eye diseases, such as diabetic retinopathy, neovascular glaucoma; renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver, mesangial cell proliferative diseases, arteriosclerosis, injuries to nerve tissue, and for inhibiting the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after mechanical devices are used to keep vessels open, such as, e.g., stents, and as immunosuppressive agents, and for supporting scar-free healing, and in senile keratosis and in contact dermatitis. 